Response to the folinic acid & supplement study - Were sufficient antioxidants employed in this study?

I just happened to look at some of the responses to the recent study on folinic acid & antioxidants in DS. I thought this response was a great response! He (Steve Hickey, PhD) explains how the study used such low doses of these nutrients that it could not benefit the children like they need to.

I also liked the last statement of his response. He says,

"Moreover, the unfortunately common propensity to give insufficient and inappropriate nutrients in trials is potentially harmful. Reports based on low intakes may prevent subjects with Down's and others from gaining benefits which are obscured by these unsuitable studies."

~ Qadoshyah

http://www.bmj.com/cgi/eletters/bmj.39465.544028.AEv2#191091

Were sufficient antioxidants employed in this study?

Steve Hickey PhD,
Lecturer
FCET, Staffordshire University, England, ST16 9DG,
Hilary Roberts PhD, Andrew Hickey



The paper by Ellis et al. illustrates a widespread problem in medicine: failure to understand the actions of antioxidants in disease. The study provides little evidence on the question of whether subjects with Down's might benefit from dietary antioxidants, because, as the authors themselves suggest, the low doses of supplements "may have been inadequate to affect biochemical pathways".

The disease mechanism for Down's syndrome arises from an increase in the activity of redox active enzymes. This leads to excess hydrogen peroxide, which causes oxidation and free radical damage in the brain. By definition, antioxidants can prevent such damage, thus potentially forming an appropriate treatment. The crucial research question is whether the appropriate dietary antioxidants can be given safely in doses sufficient to influence the pathology of the disease.

In order to influence brain pathology, dietary substances must enter the brain in sufficient concentration to act as antioxidants. The levels of primary antioxidants (vitamins C and E) used in this study were similar in magnitude to the corresponding recommended dietary allowance (RDA) levels. The subjects were young children, who would normally require lower doses than adults. However, it is important to remember that the antioxidants were intended to treat disease and, hence, we are in the realms of pharmacology rather than nutrition.

Claims for vitamin C as an antioxidant therapy involve very high doses. According to popular belief, one gram is a high dose. Contrary to this, prevention of colds (80-90%) requires doses of 10g per day or above; treatment calls for doses an order of magnitude larger. So, for example, claims for treating a cold effectively (Klenner, Cathcart, and others) [1] involve doses in the range 30g-150g per day.[2] Below these intakes, clinical effects are smaller and are more variable.[3]

The 50mg daily doses of vitamin C used in this study are substantially below pharmacological levels. Assuming a weight of 8 kg for a 7 month old child, a minimal therapeutic ascorbate dose of 140 mg/kg gives 1120 mg, i.e. approximately one gram. Thus, the dose of ascorbate employed in this study was approximately 1/20th of the minimum required. Similar considerations apply to the other nutrients. The short half-life of vitamin C means dosing frequency is also important (6 hourly or less)[2].

Subjects took 100mg of "vitamin E"; the form was not specified, although blood á-tocopherol levels were measured. Vitamin E is not a single molecule, but a range of substances that can prevent lipid oxidation in vivo. Numerous different molecules show vitamin E activity, particularly the tocopherols and tocotrienols; each has a specific pharmacology and distribution in the body. Synthetic forms, such as dl- alpha-tocopherol, are often used in studies, though they are far less effective than the naturally occurring forms.

To act as an antioxidant, vitamin E is required in higher intakes than previously realised.[4] Indeed, Balz Frei, of the Linus Pauling Institute, has described almost all clinical trials of vitamin E as "fatally flawed" because they used an insufficient dose of vitamin E.[5] To act as an antioxidant in vivo, an adult requires between 1600 and 3200 IU. Assuming 40 IU per kg, a minimum dose of about 320 IU of a high quality, natural form of vitamin E would be required for a 7-month-old child. The 100mg (synthetic?) dose employed may not act as an effective antioxidant in the brain, particularly in the absence of high levels of vitamin C.

The study employed folinic acid (0.1mg), selenium (10 ìg), zinc (5 mg), and vitamin A (0.9 mg) at low doses. Ellis et al. note that the response to folate may be enhanced by adding selected nutrients (methionine, methyl B-12, thymidine, and dimethylglycine). The specific forms of the nutrients employed was not made clear, for example forms of selenium, such as sodium selenite and methylselenocysteine, differ in pharmacology and antioxidant properties. Although we use vitamins C and E to address the main research problems, the selection and dosage of all nutrients in this study was suboptimal.

Biochemical measures in the study suggest that supplementation did not affect oxidative stress levels; this supports our suggestion that the doses employed were too low to act as in vivo antioxidants in these subjects.

The pathology of Down's syndrome has a specific oxidative mechanism. The laws of physical chemistry suggest there is little point carrying out studies using doses of antioxidants that are too low to provide the intended action: prevention of oxidation in the brain. It is possible to select suitable dietary antioxidants that can enter the brain and provide them in sufficient doses to have the desired biophysical effect.

This study did not address the role of antioxidants in Down's, as it did not use sufficient nutrients to act in vivo. Moreover, the unfortunately common propensity to give insufficient and inappropriate nutrients in trials is potentially harmful. Reports based on low intakes may prevent subjects with Down's and others from gaining benefits which are obscured by these unsuitable studies.

[1] Cathcart R.F (1985) Vitamin C, the nontoxic, nonrate-limited antioxidant free radical scavenger, Medical Hypothesis, 18, 61-77.

[2] Hickey S. Roberts H. (2004) Ascorbate: The Science of Vitamin C, Lulu press.

[3] Cathcart R.F. (1981) Vitamin C, Titration to Bowel Tolerance, Anascorbemia, and Acute Induced Scurvy, Medical Hypothesis, 7, 1359-1376.

[4] Roberts L.J. Oates J.A. Linton M.F. Fazio S. Meador B.P. Gross M.D. Shyr Y. Morrow J.D. (2007) The relationship between dose of vitamin E and suppression of oxidative stress in humans, 1388-1393.

[5]Frei B. (2007) in Vitamin E Trials 'Fatally Flawed', ScienceDaily, Sep. 26.