A question of evidence!

CamCheck highlights various issues related to complementary medicine, pseudoscience, and what constitutes good evidence before a therapeutic product can be regarded as safe or to have efficacy.

In fact, we take the approach: would I give this product to my partner or child? In other words, is there enough evidence to support the claims that the product is safe or works. Surely we do not want to take a chance on someone we love dearly?

By way of example, one of South Africa's leading suppliers of complementary medicines, Solal, sells a product for one's eyes called Lutein & Zeaxanthin (Eye Formula) and makes the following claims:

" Primary Indication: Lutein and zeaxanthin deficiency. Other Indications: They are highly protective of the eye and assist with age-related macular degeneration(AMD) and cataracts. Lutein and zeaxanthin also have cardiovascular and anti-carcinogenic effects."

http://www.solaltech.com/new/shop/index.php?act=viewProd&productId=57

No references are provided for these claims on this webpage. There is no evidence that any clinical trials were done in human beings using this product.

The UK ASA was recently faced with a similar product which also made similar claims:

"The ASA challenged whether . . .'Metabolics new Bright Eyes Formula contains Lutein, Zeaxanthin and the anthocyanadins extracted from Bilberry and Strawberry, all of which are used to keep your eyes healthy' was misleading and could be substantiated"

The UK ASA made the following comments:

"We noted that a further study concluded that higher lutein and zeaxanthin intake reduced the risk of long-term incident AMD. However, we considered that Metabolics had not proved that a supplement containing these ingredients would be absorbed and utilised by the body in the same way as the ingredients in their naturally occurring states." 

" However, we did not consider these studies sufficient evidence to substantiate the claim that the formulation of the ingredients in the Bright Eyes product maintained eye health. We considered that, in order to substantiate the claim, we would need to see robust human-based trials that showed that the formulation of the ingredients contained in the Bright Eyes Formula kept eyes healthy."

So what do you think?

  1. Was the UK ASA not given all the evidence that Solal argues supports the claims for their product?
  2. Is Solal's evidence not robust enough to prove their product works, in other words, the evidence to support the claims is simply too 'iffy'?
  3. Is the UK ASA expecting too high a level of evidence to support claims for a product?
  4. Do you agree that there must be proof that the ingredients in a "supplement" are absorbed and utilised by the body in the same way as the ingredients in their naturally occurring states (e.g. in food) if there is proof that the ingredients in their naturally occurring states do help?

You be the judge.

But we ask, based on the above example, would you give any product like this to your beloved partner or child?

This is an example that consumers face on a daily basis – having to make a decision based on a product that is unregistered, i.e., no-one except the sellers have assessed the evidence for the products safety or efficacy – or even bioavailability – in other words, as the UK ASA asks, even if the ingredient is present in the product, will it be absorbed into the body – even before one questions whether it is safe or works?


ASA Adjudication on Metabolics Ltd

Metabolics Ltd

http://asa.org.uk/ASA-action/Adjudications/2011/3/Metabolics-Ltd/TF_ADJ_49878.aspx

Ad
A leaflet for food supplements featured products called "Bright Eyes", "Colon Cleanse" and "Memory Recall". Next to pictures of the products text stated "Metabolics new Bright Eyes Formula contains Lutein, Zeaxanthin and the anthocyanadins extracted from Bilberry and Strawberry, all of which are used to keep your eyes healthy"; "COLON CLEANSE Enhances HDL thus lowering cholesterol. Detoxifies the bowel", and "MEMORY RECALL All the necessary ingredients for the nerves to make acetylcholine, the neurotransmitter principally involved with memory recall".

Issue

1. The complainant challenged whether the claim "COLON CLEANSE …

Detoxifies the bowel" was misleading and could be substantiated.

The ASA challenged whether:

2. the claim "MEMORY RECALL … All the necessary ingredients for the nerves to make acetylcholine, the neurotransmitter principally involved with memory recall" was misleading and could be substantiated;

3. the claim "Metabolics new Bright Eyes Formula contains Lutein, Zeaxanthin and the anthocyanadins extracted from Bilberry and Strawberry, all of which are used to keep your eyes healthy" was misleading and could be substantiated;

4. the heading "Is your eyesight deteriorating?" for the Bright Eyes product, implied a medicinal claim that the product could be used to prevent or cure deterioration of the eyes, and therefore required marketing authorisation from the MHRA.

CAP Code (Edition 12)
3.1
3.11
3.7
15.1
15.1.1
15.7
12.11

Response

1. Metabolics Ltd (Metabolics) accepted that the phrase "detoxifies the bowel" could be misleading and said they were happy to amend this line of text in future ads.

2. Metabolics said, regardless of the wide range of scientific publications that had shown links between memory function and the ingredients in the Memory Recall Formula product, the ad did not make any health claims in relation to this product, or any claims that the product improved memory function. They said the ad merely stated that the product contained the necessary ingredients for the nerves to make acetylcholine, and that this was the neurotransmitter principally involved with memory recall. They said that the product contained acetyl-L-carnitine and provided a study to show this acted as a metabolic cofactor in the synthesis of acetylcholine. They said it was widely recognised that acetylcholine was a key neurotransmitter involved in memory function. They also provided two studies, one on rats and one on human subjects with Alzheimers disease to substantiate this point.

3. Metabolics said that there had been a wide range of clinical studies and academic papers published that demonstrated the benefits of lutein and zeaxanthin in maintaining eye health. They submitted several papers in support of this claim.

4. Metabolics did not believe the heading "Is your eyesight deteriorating?"

implied the product could help deterioration of the eyes.

Assessment

1. Upheld

The ASA welcomed Metabolic's acknowledgement that the claim would be amended in future ads. Because the claim was unsubstantiated, we concluded it was misleading.

On this point the ad breached CAP Code (Edition 12) rules 3.1 (Misleading advertising), 3.7 (Substantiation), 3.11 (Exaggeration), 15.1 and 15.1.1 (Food supplements and associated health or nutrition claims) and 15.7 (Food supplements and other vitamins and minerals).

2. Upheld

We noted Metabolics did not believe the ad implied the product aided memory function. However, we considered that the average consumer would infer from the claim "MEMORY RECALL … All the necessary ingredients for the nerves to make acetylcholine, the neurotransmitter principally involved with memory recall" that the product contained ingredients that aided memory recall. We considered that consumers would infer from the claim in the ad that the product could aid memory recall. We further considered that, in order to substantiate the claim, we would need to see robust studies conducted on human subjects that showed the product aided memory recall in healthy adults. Because we had not seen this evidence we considered that the claim was unsubstantiated and therefore misleading.

On this point the ad breached CAP Code (Edition 12) rules 3.1 (Misleading advertising), 3.7 (Substantiation), 3.11 (Exaggeration), 15.1 and 15.1.1 (Food supplements and associated health or nutrition claims) and 15.7 (Food supplements and other vitamins and minerals).

3. Upheld

We noted the papers and studies submitted by Metabolics in support of the claim. We noted one of the studies claimed that age-related macular degeneration (AMD) was in part caused by a deficiency of lutein and/or zeaxanthin in the macular retina and went on to conclude that dietary modification could prevent or delay AMD. We noted that a further study concluded that higher lutein and zeaxanthin intake reduced the risk of long-term incident AMD. However, we considered that Metabolics had not proved that a supplement containing these ingredients would be absorbed and utilised by the body in the same way as the ingredients in their naturally occurring states.

We also noted Metabolics provided a descriptive study that concluded that most optometrists felt informed about lutein and zeaxanthin and recommended dietary modification or antioxidant supplements for AMD. A further study on AMD submitted by Metabolics noted that lutein and Zeaxanthin had a potential protective role in AMD; that dietary modification and nutritional supplementation may form important strategies in preventing progressions of disease: and that higher dietary intake of lutein and zeaxanthin reduced the risk of long-term incident AMD. However, we did not consider these studies sufficient evidence to substantiate the claim that the formulation of the ingredients in the Bright Eyes product maintained eye health. We considered that, in order to substantiate the claim, we would need to see robust human-based trials that showed that the formulation of the ingredients contained in the Bright Eyes Formula kept eyes healthy.

On this point the ad breached CAP Code (Edition 12) rules 3.1 (Misleading advertising), 3.7 (Substantiation), 3.11 (Exaggeration), 15.1 and 15.1.1 (Food supplements and associated health or nutrition claims) and 15.7 (Food supplements and other vitamins and minerals).

4. Upheld

We considered that most readers would understand from the question posed in the heading "Is your eyesight deteriorating?" that the product being advertised could help people whose eyesight was deteriorating. Because we considered this was an unauthorised medicinal claim, we considered that the ad had breached the Code.

On this point the ad breached CAP Code (Edition 12) rules 12.11 (Medicines, medicinal device, health-related products and beauty products).

Action

The ad must not appear again in its current form.

Adjudication of the ASA Council (Non-broadcast)


   

14 Responses to A question of evidence!

  1. Brent Murphy 14 March, 2011 at 11:33 am #

    Hi Harris

    In the same way as people are criticised not to refer to the YOU magazine as if it were a medical journal, I would advise you not to refer to the UK ASA as if it were one too.

    Neither the YOU magazine nor the ASA are medical authorities.

    There are MANY good references showing the benefits of lutein and zeaxanthin for eye health.

    I have compiled a 52 page document with some of the research here:

    http://www.solaltech.com/brent/LuteinZeaxanthin.pdf

    Since we are speaking of eyes, I think the saying that there are none so blind as those who will not see applies to you.

    Brent Murphy – B.Pharm (Rhodes), MPS
    Pharmacist
    SOLAL Technologies
    http://www.solaltech.com

  2. Harris 14 March, 2011 at 1:29 pm #

    Hi Brent, 

    The point about the UK ASA is that they get independent experts to review the evidence before making a decision. They are acutely aware that if they get the decision wrong, that they can be challenged in a court of law – hence their decisions have to be backed by VERY credible assessment.

     

    I do agree with Brent that “[T]here are MANY good references showing the benefits of lutein and zeaxanthin for eye health.”

     Unfortunately there are MANY good references that show that there is NO or minimal benefit.

    The fact that there is such contradictory research substantiates the simple fact: we do not have conclusive evidence! This is the conclusion of the most recent review I quote (below).

    Brent’ 52 page collection of research should be examined.

    Initially you will note some of the research is based on autopsy reports. Other papers show NO difference between supplementation and the control group (no supplementation), and yet conclude that supplementation is beneficial! Many of the studies are old. This does not invalidate them – but what does more recent studies using better research methods and technology tell us? Still controversial, i.e., no definite answer yet!

    Here are some very recent studies:

    [1]
    “Long-standing serum L levels, and in particular L supplementation, were the strongest determinants of MPOD. The hypothetical inverse association between MPOD and ARM stage was not confirmed.”

    Dietzel M, Zeimer M, Heimes B, Claes B, Pauleikhoff D, Hense HW. Determinants of Macular Pigment Optical Density and its Relation to Age-Related Maculopathy — Results from the Muenster Aging and Retina Study (MARS).  Invest Ophthalmol Vis Sci. 2011 Feb 4. [Epub ahead of print] 

    [2]
    “CONCLUSIONS: these results suggest that BCMO1 and CD36 are implicated in plasma and retina concentrations of lutein and that genetic variants in these genes can modulate blood and retina concentrations of lutein.” (In other words, may not have much to do with supplementation but genetically controlled).

    Borel P, de Edelenyi FS, Vincent-Baudry S, Malezet-Desmoulin C, Margotat A, Lyan B, Gorrand JM, Meunier N, Drouault-Holowacz S, Bieuvelet S. Genetic variants in BCMO1 and CD36 are associated with plasma lutein concentrations and macular pigment optical density in humans. Ann Med. 2011 Feb;43(1):47-59. Epub 2010 Nov 22. 

    [3]
    A positive result: 

    “CONCLUSIONS: Consumption of food-based antioxidants like β-carotene lutein and zeaxanthin seem to be useful for the treatment of macular degeneration and cataracts. Supplements of vitamin A, vitamin C, vitamin E and zinc may prevent advanced age-related macular degeneration only in high-risk individuals.”

    Agte V, Tarwadi K. The importance of nutrition in the prevention of ocular disease with special reference to cataract. Ophthalmic Res. 2010;44(3):166-72. Epub 2010 Sep 9.

    [4]
    “CONCLUSION: After oral supplementation with lutein/zeaxanthin, an increase in the macular pigmentwas detected only in areas where the macular pigmentwas present at baseline. Supplementation did not produce an increase in the area where the macular pigmentwas absent.”

    Zeimer MB, Krömer I, Spital G, Lommatzsch A, Pauleikhoff D. Macular telangiectasia: patterns of distribution of macular pigment and response to supplementation. Retina. 2010 Sep;30(8):1282-93.

    [5]
    This overview points out how complex the research and findings have been:

    “Studies of the effects of dietary supplementation, primarily with preparations including lutein and zeaxanthin, have demonstrated improvements in contrast sensitivity and visual performance under glare conditions that, in some studies, have been correlated with effects of treatment on macular pigment optical density. Results from both observational and prospective interventional studies generally support the conclusion that dietary supplements including these xanthophylls significantly decrease the occurrence of AMD and the development of nuclear lens opacities. However, there is variability in results regarding effects of dietary supplementation that may be related to limitations of long-term observational or interventional studies and which cannot be easily controlled or which may also be related in some studies to other important, yet unrecorded, diet- and lifestyle-related factors that are capable of influencing the risks for AMD and/or cataracts. CONCLUSIONS: The multiple benefits of dietary supplementation support the development and use of these preparations to promote optimal visual function and decrease risk for AMD and cataracts. Increasing understanding of the optimal approach to supplementation will depend upon results from interventional studies that also carefully evaluate and analyze well-established factors for these two conditions.” 

    Barker FM 2nd. Dietary supplementation: effects on visual performance and occurrence of AMD and cataracts. Curr Med Res Opin. 2010 Aug;26(8):2011-23. 

    In conclusion:

    One of the most recent overviews concludes: “understanding of the optimal approach to supplementation will depend upon results from interventional studies that also carefully evaluate and analyze well-established factors for these two conditions.”

    This means (1) we do not have enough answers to make conclusive claims, (2) “interventional" studies need to still be performed before any conclusions or claims can be made. 

    As usual, you the reader are free to make up your own mind!

  3. Roy 14 March, 2011 at 4:43 pm #

    The main point made by the UK ASA as I read it, was that no evidence was provided to show that the specific formulation being advertised called Bright Eyes Formula had the claimed effects. In fact they said: "we would need to see robust human-based trials that showed that the formulation of the ingredients contained in the Bright Eyes Formula kept eyes healthy."
    I think the point Harris was making was that "we would need to see robust human-based trials that showed that the formulation of the ingredients contained in Solal's Lutein & Zeaxanthin (Eye Formula) have the claimed effects."
    The other point made by the UK ASA about the bioavailability of the substances found in the Bright Eyes Formula applies equally also to Solal's Lutein & Zeaxanthin (Eye Formula).
    It seems that neither of the companies — Metabolics in the UK or Solal in SA — have done the research needed in human beings to provide robust evidence for the claims or that their respective products are adequately absorbed in humans.
    I would love to read the results of such research if it is available.

  4. Brent Murphy 15 March, 2011 at 8:34 am #

    Hi Harris
    The evidence to support the use of lutein and zeaxanthin for eye health DWARFS any evidence to the contrary. You have unfairly cherry picked studies to suit your opinion and bias against SOLAL Technologies and natural medicines generally. I would like to draw your attention to this recent study (2011):
    http://www.ncbi.nlm.nih.gov/pubmed/21296184
    Highlights:
    “Macular lutein and zeaxanthin, for example, improve visual performance (e.g., reduce glare disability and discomfort, speed photostress recovery, and enhance chromatic contrast) through purely optical means (by absorbing short-wave light anterior to the foveal cones).”
    “The eye, perhaps more than most other biological structures, has evolved an exquisite and shifting sensitivity to dietary intake throughout the lifespan, not just for its basic operation (e.g., Vitamin A for transduction), but also for its very preservation.”

    Prog Retin Eye Res. 2011 Feb 4.
    Nutritional influences on visual development and function.
    Lien EL, Hammond BR.
    Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL 61801, USA.
    Abstract
    Experiments conducted on many different species reveal a fundamental paradox about the vertebrate eye; it is damaged by its own operation. This vulnerability stems from the need to respond to visible light, often actinic, but also from the intrinsic metabolic and structural state of the eye’s internal structures. Photoreceptor outer segments, for instance, have high concentrations of diet-derived long-chain polyunsaturated fatty acids and these membrane lipids are highly prone to peroxidation due to the high oxygen tension of the outer retina. Such a high diathesis for damage would be catastrophic if it were not balanced by an equally impressive system for responding to such stressors. The retina (and to a lesser extent the crystalline lens), for instance, is especially rich in dietary antioxidants such as vitamin E, vitamin C and the macular carotenoids (lutein and zeaxanthin) putatively to retard light-induced oxidative damage. The nutrients that support both essential function (e.g., retinal, the vitamin form of vitamin A, in photopigment) and protection operate in a highly integrated manner. For instance, Vitamin E is a lipophillic chain-breaking anti-oxidant (protecting DHA-rich outer segment membranes) that regenerates itself through reaction with vitamin C (a primary anti-oxidant against aqueous radicals) and is spatially distributed in complement with the carotenoids lutein and zeaxanthin. Nor are these interactions relegated to simply providing protection and the basic elements needed for transduction. Macular lutein and zeaxanthin, for example, improve visual performance (e.g., reduce glare disability and discomfort, speed photostress recovery, and enhance chromatic contrast) through purely optical means (by absorbing short-wave light anterior to the foveal cones). The vulnerability of the eye to exogenous insult, and the sensitivity of the eye to dietary components, is not static: infants have more vulnerable retinas due to clearer lenses and higher metabolic activity; the elderly are more vulnerable due to such factors as increased inflammatory stress and a higher content of photosensitizers (such as lipofuscin) creating cascading oxidative effects. Hence, optimal dietary prophylaxis changes as the eye ages. The eye, perhaps more than most other biological structures, has evolved an exquisite and shifting sensitivity to dietary intake throughout the lifespan, not just for its basic operation (e.g., Vitamin A for transduction), but also for its very preservation.

    Regards
    Brent Murphy –B.Pharm (Rhodes), MPS
    Pharmacist
    SOLAL Technologies

  5. Brent Murphy 15 March, 2011 at 8:38 am #

    Hi Roy
    Must every manufacturer of oranges proove that the vitamin C contained in their oranges prevent survey? No.  They can rely on generic data published in medical journals on other brands of oranges.  Generic evidence is quite acceptable.  It is the standard the world over.  SOLAL relies on generic evidence which is quite acceptable and is standard practice in the food, generic medicines and complementary medicines industry.  And the evidence is compelling.
    Regards
    Brent Murphy -B.Pharm (Rhodes), MPS
    Pharmacist
    SOLAL Technologies

  6. Harris 15 March, 2011 at 9:04 am #

    Hi Brent,

    1. I am not targeting Solal per se, and not natural medicines, but claims being made out of context, or not supported by robust evidence. That Solal aggressively markets their products to consumer with these claims, results in consumers responding more to Solal than other manufacturers who lay low.

    2. I have not cherry-picked articles that support my claims (unlike you) – I have selected reviews. Can you please submit one review that supports supplementation?

    2. The article you have posted in defense of your claims has nothing to do with supplementation. There is no scientific consensus in support for supplementation – this article simply refers to how dietary intake may have a physiological impact on the eye – and dietary intake being food per se and NOT supplementation

    In fact, two of the most recent reviews on supplementation have made it very clear that we simply have too little information to guide us. In other words, there is a difference between an association and a cause.

    [1]
    "Few studies have focused on the impact of dietary lutein and zeaxanthin on retinal function and the potential to preserve vision and prevent further degeneration. This presents an opportunity for further research to determine an effective dose that delays the progression of age-related macular degeneration."
    Crit Rev Food Sci Nutr. 2009 Apr;49(4):313-26.
    http://www.ncbi.nlm.nih.gov/pubmed/19234943

    [2]
    "Increasing understanding of the optimal approach to supplementation will depend upon results from interventional studies that also carefully evaluate and analyze well-established factors for these two conditions.”
    Curr Med Res Opin. 2010 Aug
    http://www.ncbi.nlm.nih.gov/pubmed/20590393

    Harris

     

  7. Roy 15 March, 2011 at 12:21 pm #

    Hi Brent,
    Your product is not a food. You have created a new medicine by combining lutein 6 mg and zeaxanthin 2 mg into a capsule with several excipients; and recommended a dosing regimen of 1-2 capsules a day for adults, and half that for children.
    How were these amounts and dosages determined? And how do you know that they have any effect? How do you know that children should take only a half dose to achieve the same blood levels of the substances? Maybe they should take a quarter dose — or a dose based on weight? or BMI?
    You have stated that your medicine/product, in its particular fixed dose combination (FDC), is primarily intended for people with lutein and zeaxanthin deficiencies. What measurements would be used by the general public to determine these deficiencies? You do after all sell the product directly to the public. And to what extent does your FDC medicine assist in changing or improving those measurements of deficiency?
    You have stated that your FDC medicine will: assist with age-related macular degeneration and cataracts; improve eye function; reduce the risks of breast and colorectal cancers as well as atherosclerosis. The evidence for these statements using your FDC medicine (or generic) in the recommended dosage needs to be produced scientifically. I would really appreciate seeing this evidence in the form of "robust human-based trials" as required by the UK ASA for the Bright Eyes Formula claims. I would be happy to consider generic evidence if exactly the same formulation has been used in the human trial.
    You quote the pharmacokinetics of a lutein in oil solution in the "product information" — but your product is placed in capsules with several powdery excipients. Surely the bioavailability will not necessarily be the same and would have to be demonstrated?
    Your specific FDC medicine / product does not in fact seem to be supported by any "acceptable" generic evidence that I've seen.
    Your 52 page booklet on lutein and zeaxanthin does not use a systematic grading of levels of evidence in assessing each of the articles quoted. The quality of the evidence varies markedly from article to article and I for one would certainly not consider this to be compelling evidence.

  8. Brent Murphy 17 March, 2011 at 7:44 pm #

    Hi Roy and Harris
     
    Lutein and zeaxanthin are stereoisomers (mirror images) of each other – They chemically identical. They occur in that way together naturally in foods.  Therefore it is entirely appropriate to give them together that way in complementary medicines too, without necessarily viewing them as a FDC (fixed dose combination) medicine (much like a medicinal liquid food is given in the combination that occurs naturally in foods too).  Lutein and zeaxanthin are even included together in the same monograph. 
     
    Notwithstanding this I disagree that merely because one is dealing with a FDC medicine, that one necessarily can’t rely on generic data, especially if that’s how the components are usually consumed or prescribed, either naturally in foods, or intrinsic to that philosophy of medicine (eg functional medicine, where it is impossible for a single substance to treat or prevent a disease caused by a host of pathological processes, eg metabolic syndrome, heart disease etc.  Multiple substances acting via multiple pharmacologies are normally needed to address multiple pathological processes and end points).  And, if you deny that this is appropriate, then you should deny all doctors and pharmacists from prescribing multiple medicines at the same time, which is so often the case, and so often necessary.
     
    Most of our products, including lutein and zeaxanthin, are complementary medicines that contain nutrients found in foods, and thus it is often wise to give these nutrients in the way mother nature intended, combined together.  So long as stability data confirms that the product is stable in the combination, and there are no known or theoretical contra-indications, then I see no problem – just like with conventional medicine.  And we do perform stability on every single batch of our finished products, including our combination products.  And we will not release the batch if there are stability issues.
     
    If bioavailability or bio-equivalence studies become requirements in the future (which they are not anywhere in the world for any complementary medicine to my knowledge), then we are quite happy to perform those too, and we intend to perform these in any event, even if not a requirement.  But we aren’t there yet, as in many cases we have to develop the assays.  We would be the first in South Africa to do so, and one of the first in the world.
     
    Our products are manufactured in a section 22 C licensed facility and we adhere to GMP.  Almost no other complementary medicines manufacturer in SA does this.  I know of only one other manufacturer that tests products (every batch) after production.  We are also probably one of only 2 companies in SA that is develops quantitative assays for finished product testing.
     
    However we DON’T believe we have to duplicate clinical studies on the products themselves if generic data is already available on the components.
     
    With regard to your question on children’s dosages, in most cases we follow Young’s rule: age (in years)/age (in years) + 12 x normal adult dose.  There are exceptions to this where dosing children is inappropriate or dangerous, eg panax ginseng in young children.  Or SERM-like herbs with hormonal effects, eg soy isoflavones.
     
    Relating to Roy questioning our claim of lutein being used for lutein deficiencies, this comes from the Natural Medicines Database and is referenced:
     
    "LIKELY EFFECTIVE: Lutein deficiency. Taking lutein orally is effective for preventing lutein deficiency (ref 2388)."
     
    Ref 2388:
    Snodderly DM. Evidence for protection against age-related macular degeneration by carotenoids and antioxidant vitamins. Am J Clin Nutr 1995;62:1448S-61S.
     
    “LIKELY EFFECTIVE:
    This product has a very high level of reliable clinical evidence supporting its use for a specific indication. Products rated "Likely Effective" are generally considered appropriate to recommend.
    To achieve this Effectiveness Rating a product is supported by all of the following:
     
    Evidence from multiple (2+) randomized clinical trials or meta-analysis including several hundred patients (level of evidence = A).
    Studies have a low risk of bias and high level of validity by meeting stringent assessment criteria (quality rating = A).
    Evidence consistently shows POSITIVE outcomes for a given indication without significant valid evidence to the contrary.”
     
    Harris with regards your request for reviews showing effectiveness of lutein and zeaxanthin for eyes, here are a 2 REVIEWS on food based SUPPLEMENTS (SOLAL’s lutein is a SUPPLEMENT from FOOD – hence the reason the raw materials contain only 5% lutein and 5% zeaxanthin):
    http://www.ncbi.nlm.nih.gov/pubmed/20829640
    “Consumption of food-based antioxidants like β-carotene lutein and zeaxanthin seem to be useful for the treatment of macular degeneration and cataracts.”
     
    http://www.ncbi.nlm.nih.gov/pubmed/20576249
    “A growing body of evidence has established a link between lutein and zeaxanthin, higher levels of MPOD, increased visual performance, and decreased risk for AMD and other age-related eye diseases.”
     
    There are more positive reviews and clinical trials on pubmed.
     
    This is all I have to say on the issue and hereby exit this debate.
     
    Regards
     
    Brent Murphy – B.Pharm (Rhodes),MPS
    SOLAL pharmacist

  9. Harris 17 March, 2011 at 8:31 pm #

    Brent has referred to the Natural Medicines Database entry on lutein. For completeness, I am copying and pasting the entry (related to this topic only):

    "EFFECTIVENESS:"

    LIKELY EFFECTIVE
    Lutein deficiency. Taking lutein orally is effective for preventing lutein deficiency (2388).
    POSSIBLY EFFECTIVE
    Age-related macular degeneration (AMD). Epidemiological evidence suggests that people who consume higher amounts of lutein in their diet have a reduced risk of developing AMD (219,2394). Contradictory research shows no association between dietary lutein consumption and development of age-related maculopathy, which precedes macular degeneration (14007); however, people in this study had a high baseline lutein intake and therefore might not benefit as much by further increasing lutein intake.
    Preliminary clinical research suggests that taking lutein supplements 10 mg per day for 12 months can improve some symptoms of AMD such as macular pigment optical density and glare recovery, near vision acuity, and contrast sensitivity. But lutein supplements don't seem to affect the progression of AMD. It's not known whether lutein supplements can decrease the risk of AMD as effectively as dietary lutein (11798).
    Cataracts. There are epidemiological studies that suggest a reduced risk of developing severe cataracts that require surgical removal in people consuming higher amounts of lutein in their diet (2395,3219,3220). It is not known if supplemental lutein offers the same benefit."

    Of the two PubMed references that Brent posts in support of evidence for this product, is the following: “Consumption of food-based antioxidants like β-carotene lutein and zeaxanthin seem to be useful for the treatment of macular degeneration and cataracts”, by Agte et al.

    I contacted Dr Vaishali Agte and asked “[A]re you referring to supplements or food per se?”. The response was: “Regarding your querry, by food based supplements I mean supplementing foods that are natuarally rich in beta carotene.”[sic]

    And for further information:

    "Although dark green leafy vegetables contain 15-47% lutein, they have a very low zeaxanthin content (0-3%). Corn is richest in lutein (60% of total carotenoids), and orange pepper is richest in zeaxanthin (37% of total). Substantial amounts of lutein and zeaxanthin (30-50%) are also present in kiwi fruit, grapes, spinach, orange juice, zucchini, and different kinds of squash (3224)."

  10. Roy 19 March, 2011 at 2:27 pm #

    Hi Brent,
     
    Thank you for the explanation about stereoisomers. I would remind you that quinine and quinidine are also stereoisomers, but with very different effects and side effects.
     
    Your medicine is a fixed dose of 3:1 Lutein to Zeaxanthin. You have still not adequately explained the rationale for this exact proportion.
     
    I have already said that I would be more than willing to consider the evidence (data) of a generic product with the same formulation as your product. The generic should preferably also contain the same excipients (microcrystalline cellulose, magnesium stearate, magnesium silicate, silicon dioxide and colloidal silicon dioxide) in the same concentrations as your product. And of course the generic should be encapsulated in a hypromellose capsule shell. Please feel free to forward me the generic data for a product such as yours.
     
    I find it interesting that you claim that "it is often wise to give these nutrients in the way mother nature intended, combined together" — does mother nature also combine lutein and zeaxanthin with microcrystalline cellulose, magnesium stearate, magnesium silicate, silicon dioxide and colloidal silicon dioxide? And how is the absorption of the active substances affected by being encapsulated with all these excipients, compared to mother nature's food?
     
    Your product label states: "Effective 6mg Lutein and 2mg Zeaxanthin per dose, unlike other products that supply 10 times less than this". I find the word effective ambiguous. At first it seems to relate to the efficacy claims for your product, but it could possibly refer to absorption. I can only assume that you have in vivo human data to support your statement about the "effectiveness" of your product whatever meaning is used.
     
    Of course following the regulatory requirements and GMP does not guarantee efficacy of a product. Especially if the quality safety and efficacy of such a product have never been independently evaluated by the regulatory authority. Even the stability tests you say you do have not been independently evaluated. In the end it's just your word. 
     
    Please note that my question relating to lutein (and zeaxanthin) deficiency was about the measurement (diagnosis) of the deficiency per se. And in particular because the ordinary consumer can buy the product directly, how such a consumer would self-diagnose or objectively determine that they are at risk of deficiency.
     
    But most of all I am still waiting for the evidence for your product — generic or otherwise — based on robust human trials.

  11. Harris 21 March, 2011 at 9:49 am #

    In response to my request for proof that this product is safe, Brent has posted this response on an email discussion group (DrugInfo)

    Since lutein and its stereoisomer zeaxanthin are carotenoids, found in brightly coloured fruits and vegetables, your question asking me to prove that they are safe, is almost like asking me to prove that water is safe.

    There is evidence of a history of use.

    Notwithstanding this, there IS safety evidence:

    This is what Natural Medicines Database monograph says about the safety of Lutein (and zeaxanthin), with references:

    Lutein

    Also Known As: 

    Zeaxanthin

    SAFETY:

    LIKELY SAFE …when used orally and appropriately. High dietary lutein intake of 6.9-11.7 mg/day appears to be safe (3219,3220). Lutein supplements

    10 mg/day for a year have also been safely used (11798).

    PREGNANCY AND LACTATION: LIKELY SAFE …when used orally and appropriately in amounts found in foods. The high end of dietary lutein intake ranges from

    6.9-11.7 mg/day (3219,3220).

    3219

    Brown L, Rimm EB, Seddon JM, et al. A prospective study of carotenoid intake and risk of cataract extraction in US men. Am J Clin Nutr 1999;70:517-24.

    3220

    Chasan-Taber L, Willett WC, Seddon JM, et al. A prospective study of carotenoid and vitamin A intakes and risk of cataract extraction in US women. Am J Clin Nutr 1999;70:509-16.

    11798

    Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degermation: the Veterans LAST study (Lutein Antioxidant Supplement Trial). Optometry 2004;75:216-30.

    http://www.ncbi.nlm.nih.gov/pubmed/15117055?dopt=Abstract

    To achieve a likely safe rating:

    LIKELY SAFE:

    This product has a very high level of reliable clinical evidence showing its safe use when used appropriately. Products rated Likely Safe are generally considered appropriate to recommend.

    To achieve this Safety Rating a product is supported by all of the

    following:

    Safety data is available from multiple (2+) randomized clinical trials or meta-analysis or large-scale post-marketing surveillance including several hundred patients (level of evidence = A). Or the product has undergone a safety review consistent with or equivalent to passing a review by the Food and Drug Administration (FDA), Health Canada, or similarly rigorous approval process.

    Studies have a low risk of bias and high level of validity by meeting stringent assessment criteria (quality rating = A).

    Studies adequately measure and report safety and adverse outcomes data and consistently show no significant serious adverse effects without valid evidence to the contrary.

    My response

    Hi Brent,

    As you know, I usually rate Natural Medicines Database highly.

    So I am surprised that some of their references are not entirely appropriate.

    For example:

    "High dietary lutein intake of 6.9-11.7 mg/day appears to be safe (3219,3220)."

    This study, 3219, Brown et al., utilised: "a detailed dietary questionnaire was used to assess intake of carotenoids and other nutrients". NO supplements were used. "Among specific foods high in carotenoids, broccoli and spinach were most consistently associated with a lower risk of cataract." The second study Chasan-Taber et al., similar to that of Brown et al.,  but conducted on women was similar: "Lutein and zeaxanthin and foods rich in these carotenoids may decrease the risk of cataracts severe enough to require extraction."

     

    The third reference is for this statement:

    "Lutein supplements 10 mg/day for a year have also been safely used (11798)."

    This study by Richer et al. used 10 mg lutein daily for 12 months above normal food lutein intake (levels not recorded). The authors conclude: "Further studies are needed with more patients, of both genders, and for longer periods of time to assess long-term effects . . . "

     

    So if these studies deemed lutein intake found in foods to be safe, and measured up to 11.7mg/day, how safe will it be to add Solal's formula which adds another 12 mg/day (2 caps b.d.) over and above someone eating a fairly high lutein "normal" diet? Can one conclude that sufficient robust trials have concluded lutein long term use and at 12 mg/day above normal daily intake to be safe? And considering that many patients will increase their intake of lutein rich foods on top of taking lutein supplements, can you assure consumers with absolute confidence that short and long term studies have been conducted to your satisfaction?

  12. Brent Murphy 22 March, 2011 at 2:27 pm #

    Hi Harris and Roy.

    Harris regarding your question on safety:

    SAFETY:
    The council for responsible nutrition has, based on available scientific data, estimated the safe upper level (SUL) for human consumption, at which no known toxicity for lutein will occur, as being 20mg daily.

    The typical US diet supplies 1-3mg lutein and zeaxanthin combined daily.

    References:
    * Mares-Perlman JA, Fisher AI, Klein R, et al. Lutein and zeaxanthin in the diet and serum and their relation to age-related maculopathy in the third National Health and Nutrition Examination Survey. Am J Epidemiol 2001;153:424–32.[Abstract/Free Full Text] http://www.ajcn.org/cgi/ijlink?linkType=ABST&journalCode=amjepid&resid=153/5/424

    * Nebeling LC, Forman MR, Graubard BI, Snyder RA. Changes in carotenoid intake in the United States: the 1987 and 1992 National Health Interview Surveys. J Am Diet Assoc 1997;97:991–6.[Medline] http://www.ajcn.org/cgi/external_ref?access_num=9284877&link_type=MED

    * Nebeling LC, Forman MR, Graubard BI, Snyder RA. The impact of lifestyle characteristics on carotenoid intake in the United States: the 1987 National Health Interview Survey. Am J Public Health 1997;87:268–71.[Abstract/Free Full Text] http://www.ajcn.org/cgi/ijlink?linkType=ABST&journalCode=ajph&resid=87/2/268

    South Africans diets are typically Western American type diets, and it is logical and safe to assume our dietary consumption of lutein is similar to the USA.

    Therefore at SOLAL’s dosage recommendation of 6-12mg daily in supplement form, this equates to 7-15mg daily from all sources, well below the 20mg daily USL.

    CRN Risk Assessments For Non-Essential Nutrients Published

    WASHINGTON, D.C., July 7, 2006 — The Council for Responsible Nutrition (CRN) has authored risk assessments for coenzyme Q10 (CoQ10), carotenoids lutein and lycopene, and creatine monohydrate. The risk assessments, published by the peer-reviewed journal Regulatory Toxicology and Pharmacology, were co-authored by CRN scientists John Hathcock, Ph.D., and Andrew Shao, Ph.D., to ensure regulators worldwide have a science-based guideline available to determine safe upper levels for these popular non-essential nutrients in dietary supplements.

    “Coenzyme Q10, lutein, lycopene and creatine are becoming more popular and more prevalent in dietary supplements and a safe upper level has not as of yet been established by governing bodies for these nutrients,” explains Dr. Shao, co-author of the risk assessment papers and vice president of scientific and regulatory affairs for CRN.

    Applying a safety evaluation method he developed and which has been recognized internationally as a scientifically valid way to evaluate nutrient safety, CRN’s Dr. Hathcock, vice president of scientific and international affairs, along with his co-author Dr. Shao, reviewed clinical trials for the non-essential nutrients CoQ10, lutein, lycopene, and creatine to determine the safe upper level for supplements (ULS) for each. The values noted in the risk assessments are identified as the ULS, since dietary intakes from food sources were not taken into consideration.
    The ULS values were derived using basic elements of the U.S. Food and Nutrition Board’s (FNB) methods as well as the observed safe limit (OSL) method, developed by Dr. Hathcock and now used as the highest observed intake (HOI) by the Food and Agriculture Organization and World Health Organization.

    For each nutrient, Drs. Hathcock and Shao reviewed only randomized controlled trials (RCTs) conducted in humans, using uncontrolled trials and animal data as supportive information only. For CoQ10 the authors arrived at a ULS of 1,200 mg per day. For lutein the authors concluded that a ULS of 20 mg per day should be proposed for this carotenoid. For lycopene, the authors arrived at a ULS of 75 mg per day. Creatine was assigned a ULS of 5 grams per day.

    Upper levels do not suggest that supplements taken above the level identified are unsafe, nor do they constitute a recommended intake. They simply identify a level at which there is “no known toxicity for these nutrients,” said Dr. Hathcock. “Risk assessments allow us to put forth science-based guidelines for safety levels. Since there are no observed adverse effects for these nutrients, governing bodies haven’t set upper limits, leaving the door open for regulatory mischief. We’ve seen that happen before, especially in Europe where countries have tried setting limits a hundred times lower than observed safe levels, using, implicitly or overtly, the precautionary principle instead of science as justification. These risk assessments are necessary to ensure that science, not rhetoric, leads the way when it comes to safety.”

    The recently published risk assessments are currently available online through the International Society for Regulatory Toxicology and Pharmacology (ISRTP) and will be published in an upcoming issue of Regulatory Toxicology and Pharmacology, the official journal of ISRTP. Drs. Hathcock and Shao are also working on risk assessments for carnitine, and glucosamine and chondroitin sulfate, which have been accepted for upcoming publication in Regulatory Toxicology and Pharmacology.

    Dr. Hathcock is also the author of the CRN publication, Vitamin and Mineral Safety, 2nd Edition, which provides an academic review of safety levels for 28 vitamins and minerals, with methodology, including CRN’s approach, on assessing safety along with a review of governmental and regulatory safety conclusions.
    ________________________________________

    Note to Editor: The Council for Responsible Nutrition (CRN), founded in 1973, is a Washington, D.C.-based trade association representing dietary supplement industry ingredient suppliers and manufacturers. CRN members adhere to a strong code of ethics, comply with dosage limits and manufacture dietary supplements to high quality standards under good manufacturing practices.

    Furthermore I would like to point out that lutein has been given GRAS (generally regarded as safe) status for human consumption, by the Food and Drug Administration in the USA, based in part by studies that show that there are NO SIDE EFFECTS (in rats) at a dose of 200mg/kg body weight/ per day (that’s NO SIDE-EFFECT dose, not a LD50).
    See: http://www.accessdata.fda.gov/scripts/fcn/gras_notices/805174A.PDF

    Extrapolated to humans this would be 14 400mg dose of lutein per day. The resultant CRN recommendation of 20mg USL for humans has built in a 720 fold safety margin! (20mg x 720 = 14 400)
    ________________________________________

    Roy,

    Regarding your question on evidence:

    FOOD vs SUPPLEMENT FORM:

    This from Natural Medicines Database, showing that supplement forms and food-derived lutein is similar, and specifically that marigold extract in supplement form causes a 5-fold serum level increase (SOLAL uses marigold lutein extract, comprising 5% lutein):

    [ALL CAPITALISATION IS MY (BRENT’S) INSERTION]
    “Lutein 6 mg/day from SUPPLEMENTS, including lutein ester, have a bioavailability similar to lutein from spinach. These sources increase serum lutein levels by about 2 times after 10 days. Lutein from enriched eggs have the greatest bioavailability. Lutein-enriched eggs providing 6 mg/day for 10 days increase serum levels about 4 times (15343). Lutein 15 mg/day from marigold extracts [SOLAL’s LUTEIN COMES FROM MARIGOLD EXTRACT] causes a 5-fold increase in lutein serum levels in healthy volunteers (14053). Other factors, such as formulation dissolution [SOLAL PERFORMS DISSOLUTION TESTS AS STANDARD FOR ALL OUR PRODUCTS] and dietary fat intake, can play a significant role in lutein bioavailability (6133,15345). Lutein ester is better absorbed when taken with a high-fat meal (6133).”

    So once again I assert that the generic evidence I have already supplied and that is available here, is adequate:

    http://www.solaltech.com/brent/lutein/

    Regards

    Brent
    —————
    Brent Murphy – B.Pharm (Rhodes), MPS
    Pharmacist

  13. Roy 23 March, 2011 at 7:53 am #

    Brent
     
    It's interesting that you have not in fact "exit[ed] this debate" as per your comment (#8).
     
    You have still not provided the generic evidence for a fixed dose combination of the stereoisomers lutein:zeaxathin 3:1 formulated with excipients similar to your product's excipients in a vegetable-based capsule. You separate the actives in the name and labelling of your product, although the Natural Medicines Database does not. Your product's actives seemingly come from different sources – this is not clear.
     
    You have not yet provided robust human evidence that your formulation (or generic) provides similar serum levels to those in the studies you quoted; or that your formulation (or generic) actually does "assist with age-related macular degeneration and cataracts; improve eye function; reduce the risks of breast and colorectal cancers as well as atherosclerosis" in humans.
     
    Relying on data and information provided by a trade body like the CRN must be treated with suspicion. It's a bit like accepting data and information provided by the Health Products Association's scientists in South Africa. It's also like considering clinical trials sponsored by the pharmaceutical industry with suspicion.
     
    I note that you have directly extrapolated a dose from rats to humans for upper limits of safety. Animal studies can however only be used as a guide to determining the doses that could be used in human studies and not as "evidence" that the doses are safe in humans. This has led to disasters in the past.
     
    I would remind you that generic medicines (such as you claim your product to be) must meet the requirements of both pharmaceutical equivalence and therapeutic evidence as defined in the Medicines Act. Again I would point out that your product has not been independently assessed for quality, safety, or efficacy by a regulatory authority. I must assume that you have chosen to not submit data to the regulatory authority for evaluation of these parameters, but that you take full responsibility for these parameters yourself as the responsible pharmacist.
    I still don't know how a consumer buying your product for it's primary indication of lutein and zeaxanthin deficiency would know that s/he in fact has such a deficiency? Or how you as the seller and responsible pharmacist could be sure that the consumer is purchasing it (via your website or in a health shop) for the stated indications.
     
    I have asked these and similar questions repeatedly, and still do not have clear answers.

  14. Harris 23 March, 2011 at 8:59 am #

    I want to make the point of how we all can be so side-tracked by one line of reasoning and forget others that may also be critical – for example, whether a low serum level (or intake) is ASSOCIATED with, or the CAUSE of a disease. I submit that I forgot to point this out to readers in this discussion! 

    Here is the conclusion of a recent paper:

    " The AMD patients and control subjects responded similarly to a diet high in lutein and zeaxanthin; plasma carotenoid concentrations increased greatly in both groups, and the transport of carotenoids by lipoproteins was not significantly different between the groups. This finding suggests that abnormalities in the metabolism of lutein and zeaxanthin in AMD may reside in the uptake of lutein and zeaxanthin from the plasma and transport into the retina." [1] An argument supported by a more recent publication. [2] 

    I accept this study needs to be replicated, but nevertheless! 

    [1]
    Am J Clin Nutr. 2007 Mar;85(3):762-9.

    Effect of dietary lutein and zeaxanthin on plasma carotenoids and their transport in lipoproteins in age-related macular degeneration.
    Wang W, Connor SL, Johnson EJ, Klein ML, Hughes S, Connor WE.
    http://www.ajcn.org/content/85/3/762.full 

    [2]
    " The biological mechanisms governing retinal capture and accumulation of lutein and zeaxanthin, to the exclusion of other carotenoids, are still poorly understood. Although these mechanisms remain unclear, it is possible that selective capture of these carotenoids is related to lipoprotein, or apolipoprotein, function and profile. Xanthophyll-binding proteins appear to play an important role in the retinal capture of the xanthophyll carotenoids. The Pi isoform of GSTP1 has been isolated as a specific binding protein for zeaxanthin. The binding protein responsible for retinal uptake of lutein remains elusive."

    Surv Ophthalmol. 2008 Jan-Feb;53(1):68-81.
    Transport and retinal capture of lutein and zeaxanthin with reference to age-related macular degeneration.
    Loane E, Nolan JM, O'Donovan O, Bhosale P, Bernstein PS, Beatty S. Macular Pigment Research Group, Waterford Institute of Technology, Waterford, Ireland.
    http://www.ncbi.nlm.nih.gov/pubmed/18191658

     

    To readers of this posting: you may be left confused by the opposing views expressed here. One set is by Brent Murphy, a pharmacist – but also with a financial interest in his company’s product; the other, by Dr Harris Steinman and Prof Roy Jobson, both arguing from their perspective of what constitutes acceptable robust evidence required to ensure the safety of a product, and whether that product will deliver on the claims being made. Some readers may read this posting blindly because of favouring complementary medicine over “orthodox” medicine, and vice versa. I ask that you do neither – that you read the arguments of both sides carefully and make your own decision. Put yourself in this position: you are the parent of someone who might need a product that makes the claims this one does. Are you satisfied that the product’s safety has enough short term and long term safety? Are you satisfied that this product will work for her/his condition?

    This correspondence is now closed.

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.