Questions to StemEnhance

Posted 2 July 2010 

For Attention:

Mr Ray Carter:

CEO: StemEnhance

23 August 2009

I am writing in response to your letter dated 31st July 2009. Apparently, it was sent in response to my letter to Ms. Livingston where I asked for information regarding the claims made in relation to your product Stem Enhance. It is unfortunate that in response I am threatened with a lawsuit even though I am fully entitled under South African law to request the information regarding your product. Ms Livingston acknowledged that there is not a single trial to confirm the efficacy for the claims being made for StemSport, for the dosage recommended, etc.

I became aware of your product because you approached the media to promote your products without having addressed the concerns of any of the professional medical community in South Africa actively working in this area. I am entitled as part of that professional community as well as a member of the public to address those concerns. 

I sent Ms Livingston a deconstruction of your “seminal” study and would have expected a concise and scientific response to the questions and arguments raised and am disappointed that instead it elicited a threatening letter. We could perhaps have a more constructive dialogue if you would provide me with scientific responses to these points. I am not the only scientist who finds your scientific evidence to be of inadequate quality in support of the claims for this product, so your response would be helpful to others as well. Indeed, I surmise that my arguments are supported by the vast majority of internationally recognised experts doing research in this field. 

It would also be helpful if you would clarify the status regarding the registration of your product with the MCC. To my knowledge, your product is NOT registered with the MCC, it simply has a number indicating receipt of the documents by the MCC – this is not considered a registration. I also point out that statements made in your patent, and claims made at the meeting I attended, clearly indicate the intended claims being made by your product, thus invoking the South African Medicines Act: 

For ALL products making therapeutic claims, the Medicines Act is relevant / applies.

The definition of a medicine according to the Act is:

‘medicine’ means any substance or mixture of substances used or purporting to be suitable for use or manufactured or sold for use in-

(a) the diagnosis, treatment, mitigation, modification or prevention of disease, abnormal physical or mental state or the symptoms thereof in man; or

(b) restoring, correcting or modifying any somatic or psychic or organic function in man, and includes any veterinary medicine;” [my emphasis] 

I also draw your attention to a recent court case, in which Judge Zondi clearly invoked this act in relation to a product claimed to be a complementary medicine, or a supplement.  In that case, the company making claims for their product was effectively shut down. 

In conjunction with internationally recognised stem cell scientific experts, a senior academic pharmacologist who serves on the Medicines Control Council, and a number of other interested scientists, we have compiled a list of questions for which we would kindly request answers. These questions are those that have been raised and therefore your answers will be used to correct any misinformation. 

Yours, 

Dr Harris Steinman

 

Comments and Questions 

Status of Christian Drapeau

1. Comment and/or Question:

I asked the following question to Montreal Neurological Institute administration: “Christian Drapeau, MSc, claims to have a Masters of Science in Neurology and Neurosurgery from Montreal Neurological Institute. Is this fact indeed correct?” 

This is the response I received:

“Dear Dr. Steinman,

Thank you for your email. I do not know if Christian Drapeau received a degree from McGill (I am not sure if I can find this information). As far as I know he does not collaborate with any of our faculty.”

Communications Officer/Relationniste Montreal Neurological Institute and Hospital Institut et hôpital neurologiques de Montréal 3801, rue University, Montréal (Québec) H3A 2B4 T 514 398-1902  F 514 398-8072 www.mni.mcgill.ca 

a.) Does Christian Drapeau actually have a MSc from the Montreal Neurological Institute?

b.) If so, why does the Montreal Neurological Institute does not acknowledge Drapeau’s degree?

c. One would expect that if Christian Drapeau’s breakthrough research would be acknowledged by members of his alma mater yet none were able to including the statement that “. . . he does not collaborate with any of our faculty”. Could this be put into context? 

 

Studies on StemEnhance

2. Comment and/or Question:

The official StemEnhance website reports on the article “Triple-Blind Randomized Placebo-Controlled Study of the Effect of StemEnhance on Bone Marrow Stem Cell Mobilization by Christian Drapeau, MSc.” but may be referring to the Jensen et al study, which was a double-blind study. Is this deliberate marketing misinformation, or does the “Triple-Blind” refer to another study, in which case, has this study been published in an internationally recognised peer-reviewed scientific journal? If so, where? If not, why not? 

If the “Triple-blind” study listed on many websites is meant to refer to the Jensen GS, et al. / Cardiovascular Revascularization Medicine 8 (2007) 189–202 191 study, is it not unethical for Christian Drapeau to be taking sole credit for this study as seen on many websites, including the StemEnhanceBiz website? 

If the “Triple-blind and “Double-Blind” studies are the one and the same, if not deliberate misinformation, what is StemEnhance doing to correct this apparent difference? 

3. Comment and/or Question:

Please list one or more reproducibility studies conducted by independent internationally recognised research institutes and published in peer-reviewed journals that confirms the findings that StemEnhance results in the release of adult stem cells into the circulation in humans. 

4. Comment and/or Question:

Please explain why the release of adult stem cells as a result of the ingestion of StemEnhance is conceived as being a positive response rather than an adverse response, i.e., a systemic effect in response to a toxin. 

5. Comment and/or Question:

Please list at least one study evaluated by an independent internationally recognised scientific establishment that confirms that the release of adult stem cells is uniquely a result of StemEnhance and does not occur to an equivalent or greater degree following the ingestion of an average mix or intake of individual vegetables or fruits, e.g., broccoli, spinach, mushrooms, blueberries etc. For example, I am aware that there is a patent for another product, containing among other things, blueberries, that claims to release adult stem cells (US Patent 7442394). 

6. Comment and/or Question:

Assuming that StemEnhance does release adult stem cells, please list one or more studies conducted by yourselves or independent internationally recognised research institutes and published in peer-reviewed journals that confirm the claims being made for StemEnhance:

1. that the adult stem cells resulting from StemEnhance reach other organs, i.e., are not eliminated by the body

2. that the released stem cells exert a positive effect, i.e., become differentiated into the local cell type and incorporatedi into the organ in question. 

7. Comment and/or Question:

It is striking that in the only study demonstrating the “efficacy” of StemEnhance’s ability to release adult stem cells (Jensen GS, et al. / Cardiovascular Revascularization Medicine 8 (2007) 189–202 191), individual variability was not listed or discussed except an average increase in CD34+ of 25% noted for 9 subjects (3 of 12 were excluded – (or was it 3 of 15)). It is well known that in pharmacological studies, to support a product’s claims of efficacy, this method of summarising data may be deliberately employed to give credibility to results when in fact inter-individual results are not significant (not necessarily in this study). To elaborate: If 1 of the 9 experienced a 225% increase in stem cell release, and none of the other 8, the average would be determined as 25%. Similarly this would apply if 2 of 9 experienced a 112% increase, and none of the other 7 subjects. 

Can the authors release the data listing the individual results for each individual, and support this by an affidavit signed by each author to confirm that these results are unaltered? 

8. Comment and/or Question:

The extract treatment shows an increase CD34+ cells, an increase from 0.062% to 0.085%. The placebo treatment resulted in no increase, but the initial percentage of circulating CD34+ cells was already as high as AFTER StemEnhance treatment. 

Can you explain this discrepancy, i.e., the placebo group mean was around 0.085% before the study and the study group 0.062%? 

Can anything meaningful be taken from this result? 

Was the data obtained from the mean value of the total placebo group? In other words, what are the data of the outliers? 

9. Comment and/or Question:

The Jensen et al. study and the “Triple-Blind Randomized Placebo-Controlled Study of the Effect of StemEnhance on Bone Marrow Stem Cell Mobilization by Christian Drapeau, MSc.”  have as exclusion criteria, “Under 20 or over 65 years of age”. In clinical studies, it is vital that conclusions are not inferred and that the studies are conducted on correct target groups, i.e., a study of the efficacy of paracetamol in individuals aged 65 and older cannot be extrapolated to adolescents aged 15. 

Explain the rationale for extrapolating the findings of 12 individuals aged between 20 and 65 to your advertising claims aimed at all ages. 

As results from only 12 individuals are assessed, and if equally distributed, the maximal number of individuals of one sex would be 6 or less, is it scientifically correct to therefore extrapolate findings of such a small group to the general group of that sex? 

Was there a statistical significance in the results between the different sexes?

Were other confounding variables such as hormonal factors taken into consideration? 

10. Comment and/or Question:

The study on stem cell mobilization in annexure III lacks scientific rigueur:

(a) on what basis were the patient exclusion criteria chosen;

(b) the measurements were only made up to 120 minutes – what happens thereafter;

(c) what evidence is there that a 25-30% increase in the number of circulating CD34+ cells for 120 minutes is of physiological importance;

(d) what is the placebo;

(e) the May 2005 study referred to is anecdotal. 

Please comment on these aspects. 

11. Comment and/or Question:

“Basically I think that it’s true that higher levels of endothelial progenitor cells have been associated with better long-term [health] outcomes,” said Kreton Mavromatis at Emory University. But there is no causative study showing those cells are responsible for improved health, Mavromatis told The Scientist. (http://sci.rutgers.edu/forum/archive/index.php/t-82032.html) 

Can you list studies that contradict this statement?

12. Comment and/or Question:

The study by Jensen et al, concludes: “Empirical observations suggest that consumption of StemEnhance for longer periods of time might indeed bring significant improvement in various health conditions, including specific neurodegenerative diseases, chronic obstructive pulmonary disease, kidney insufficiency, and other degenerative problems. However, rigorous studies are necessary to examine the effects of StemEnhance on specific degenerative diseases.” 

What is the justification for StemEnhance, and the many websites marketing your product, including those of StemEnhance distributors, making claims when the single study on the efficacy of StemEnhance states explicitly “[H]owever, rigorous studies are necessary to examine the effects of StemEnhance on specific degenerative diseases”? 

13. Comment and/or Question:

The study on cardiotoxin-induced muscle injury (Annexure IV) is flawed for several reasons:

(a) it is assumed that an increase in the number of fluorescently-labeled cells is indicative of “repair”; this assumption is incorrect, and there are several other explanations;

(b) the increase in muscle strength is anecdotal and needs to be quantified. 

Please comment on these arguments. 

14. Comment and/or Question:

Please list one or more studies conducted and published in peer-reviewed journals that confirm the short term and long term safety of StemEnhance and StemSport, as used in their suggested dosages, in humans (NOT animal models). 

15. Comment and/or Question:

“Drapeau said he has not seen any evidence the product causes harm, and is hesitant to produce too much data saying it works, out of fear the US Food and Drug Administration will revoke its status as a dietary supplement — where it’s available to everyone sick and well – and consider it a drug that requires a prescription. “We have not yet documented in a rigorous manner the health benefits [of StemEnhance] essentially because they are so obvious, and I am concerned if we get data showing the product is effective… we will be in a difficult position with the FDA,” Drapeau said.” (http://sci.rutgers.edu/forum/archive/index.php/t-82032.html) 

It is ethical or correct for a scientist to state “[W]e have not yet documented in a rigorous manner the health benefits [of StemEnhance] essentially because they are so obvious”, i.e.,

(a) to state that anecdotal evidence is sufficient to make claims for a product, and (b) for a scientist and company to market a “health” product without any “documented in a rigorous manner the health benefits”? A lesson from history is that blood-letting as a cure all was promoted by the same methods – anecdotal stories. 

 

Microcystins

 16. Comment and/or Question:

In the publication, “Dietrich D, Hoeger S. Guidance values for microcystins in water and cyanobacterial supplement products (blue-green algal supplements): a reasonable or misguided approach? Toxicol Appl Pharmacol. 2005 Mar 15;203(3):273-89”, caution is advised regarding, among other, microcystin content and long term effects of this toxin. 

Microcystins are known to cause liver toxicity. They have also been shown to damage DNA at low levels of exposure. The long-term consequences of microcystin exposure have not been well-researched. While microcystins have been the primary concern, analyses of algae blooms around the world have revealed a rather high diversity of other bioactive compounds including inhibitors of enzymes (cytoxins) and numerous unidentified substances. Zhang, et al. published an article in the January 2007 issue of Environmental Toxicology that shows that microcystins not only accumulate in the liver and other tissues of adults, but are passed on to their offspring. 

Further concern has been raised by the German Commission in their position statement “Microcystins in algae products used as food supplements – DFG – Senate Commission on Food Safety” (http://www.dfg.de/aktuelles_presse/reden_stellungnahmen/2007/download/sklm_microcystine_07_en.pdf) and by Eisenbrand G; Senate Commission on Food Safety (SKLM), German Research Foundation (DFG). Microcystins in algae products used as food supplements. Mol Nutr Food Res. 2008 Jun;52(6):735-6, states: “products from the algae species Aphanizomenon flos-aquae (AFA) in the form of powders, pills, capsules or tablets are advertised as food supplements in the internet, in printed media and non-scientific publications”, and concluded that  AFA algae marketed in Europe originate from Upper Klamath Lake, Oregon, USA” and that “[A]lthough only an inadequate number of samples have been investigated so far, the results indicate that from the more than 60 congeners, primarily microcystin-LR (approx. 90%) is present in AFA algae products.” 

The summary goes on to state: “On the basis of the PTDI value established by the WHO, a guidance value of 1 μg microcystin-LR/g AFA algae was issued for AFA algae in the USA. This was based on the assumption that algae products are the only dietary source of microcystins and that the daily intake of AFA algae is 2g per person (60 kg). However, microcystin-LR concentrations of up to 33 μg/g were measured in commercially available AFA algae products. In the USA, a total of 87 samples were screened for microcystin-LR between 1996 and 1999; 70% of the measured values were higher than the guidance value of 1 μg/g. An intake of up to 3 g AFA algae/day, as recommended by the manufacturers, thus may lead to a considerable exceedance of the PTDI of the WHO even without taking into account a possible additional intake via drinking water.” 

The conclusion of this document states unequivocally: “Microcystin-LR is a potent hepatotoxic agent. There is evidence that microcystin-LR may act as a tumour promotor in the rodent liver. There is also evidence that microcystin-LR can initiate DNA damage, both in vitro and in vivo. However, adequate studies on the long-term toxicity and carcinogenicity of microcystin-LR are lacking. In view of the available contamination data, the intake of AFA algae products as recommended by manufacturers may result in the exceedance of the PTDI for microcystin-LR. Therefore, according to the current level of understanding, a human health risk can not be excluded if such products are consumed regularly.” 

In a 2008 review, the following statement is made by the first author of the German Commission report: “For an adequate assessment of microcystin-LR in algae products used as food supplements, data on long-term toxicity and carcinogenicity is required.” Eisenbrand G; Senate Commission on Food Safety (SKLM), German Research Foundation (DFG). Microcystins in algae products used as food supplements. Mol Nutr Food Res. 2008 Jun;52(6):735-6. This conclusion was based largely on the 45 page review compiled by the Swiss Federal Office of Public Health, Food Toxicology Section, Zürich. (Annex to the SKLM opinion “Microcystins in Algae Products Used as a Food Supplement” – Engeli B. Overview and evaluation of the literature on microcystins. Swiss Federal Office of Public Health, Food Toxicology Section, Zürich) 

I therefore request documentation from independent laboratories using LC MS/MS technology that is known to identify microcystin-LA, showing that each batch of product is free of microcystins. Since the amount of contamination varies widely, spot checking of batches at intervals is insufficient.  Elisa testing, which does not identify microcystin-LA is insufficient. ELISA analysis significantly underestimates the amount of microcystins present in a product. (Bruno M, Fiori M, Mattei D, Melchiorre S, Messineo V, Volpi F, Bogialli S, Nazzari M. ELISA and LC-MS/MS methods for determining cyanobacterial toxins in blue-green algae food supplements. Nat Prod Res. 2006 Jul 20;20(9):827-34) 

Gilroy et al. (Gilroy DJ, Kauffman KW, Hall RA, Huang X, Chu FS. Assessing potential health risks from microcystin toxins in blue-green algae dietary supplements. Environ Health Perspect. 2000 May;108(5):435-9) point out that microcystins were detected in 85 of 87 samples from Lake Klamath tested, with 63 samples (72%) containing concentrations > 1 microg/g. They state “ . . . preliminary data showed differences within some product samples of up to 99%, we further investigated the potential for batch heterogeneity. A comparison of two samples from each of six different batches found unremarkable differences in most of the samples, but found a large difference (> 100%) in one sample. 

I am aware that Carmichael et al. (Carmichael WW, Drapeau C, Anderson DM. Harvesting of Aphanizomenon flos-aquae Ralfs ex Born. & Flah. var. flos-aquae (Cyanobacteria) from Klamath Lake for human dietary use. J Appl Phycol 2000;12(6): 585-595) suggest that techniques for separating toxic cyanobacteria from the A. flos have been developed. However, Saker et al.’s work published 5 years later demonstrated the persistence of microcystin contamination in the products on the market. (Saker ML, Jungblut AD, Neilan BA, Rawn DF, Vasconcelos VM. Detection of microcystin synthetase genes in health food supplements containing the freshwater cyanobacterium Aphanizomenon flos-aquae.) 

I also refer you to the following figures: (images not shown here, but demonstrates high levels of this toxin) 

TECHNICAL MEMORANDUM: Microcystis aeruginosa Occurrence in the Klamath River System of Southern Oregon and Northern California. February 3, 2006

(http://www.yuroktribe.org/departments/ytep/documents/KannFinalYurokMsaeTechMemo2-3-06.pdf) 

According to my information, at last report, your company was continuing to use Elisa testing, which does not identify microcystin-LA – one of the two main microcystins common to Klamath Lake algae. 

Please comment. 

Are you able to supply results of testing for microcystin for every batch produced by StemEnhance, and if not, why not? 

17. Comment and/or Question:

I am not aware that any post-marketingsurveillance of potential adverse effects for Klamath algae (nor StemEnhance) was in place, and what evidence is there to confirm that there has not been a build up of this toxin in the livers of chronic users of StemEnhance? 

18. Comment and/or Question:

I am aware that you place a lot of evidence on anecdotal reports which claim that you have not had a single case of toxicity related to the product. However, scientific evidence is clear that supplements and complementary products, because of their distribution channels, have very poor post-marketing surveillance and so if reactions have occurred, they may not have been attributed to StemEnhance since doctors have not yet been alerted to this risk factor. Your position that no toxic reactions have been reported to StemEnhance is no different to that given for a number of Chinese and herbal products, e.g., comfrey, and the Chinese ingredients used in Herbalife, that have recently, as a result of western medicine post-surveillance, shown to have toxicity. 

Schoepfer AM, Engel A, Fattinger K, Marbet UA, Criblez D, Reichen J, Zimmermann A, Oneta CM. Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife products. J Hepatol 2007 Oct;47(4):521-6.

Elinav E, Pinsker G, Safadi R, Pappo O, Bromberg M, Anis E, Keinan-Boker L, Broide E, Ackerman Z, Kaluski DN, Lev B, Shouval D. Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity. J Hepatol 2007 Oct;47(4):514-20.

Determination of pyrrolizidine alkaloids in commercial comfrey products (Symphytum sp.).

Yeong ML, Swinburn B, Kennedy M, Nicholson G Hepatic veno-occlusive disease associated with comfrey ingestion J Gastroenterol Hepatol 1990;5(2):211-214

Rode D. Comfrey toxicity revisited. Trends Pharmacol Sci 2002;23(11):497-9 

Similarly, no-one attributed adverse effects to aflatoxins in maize – it took many, many years to demonstrate this. The point regarding aflatoxins is significant – it points to cumulative cause and effect one to two decades after exposure, and proof of concept that adverse effects were not ascribed to aflatoxins several decades later.

Your comment that “you have not had a single case of toxicity related to the product” is contradicted by reports made to the FDA, and to put your claims in context, I refer you to Gilroy et al: “[F]or information regarding the safety of dietary supplements, the FDA relies heavily on reports to its MedWatch program (51). Although this program provides useful information to the FDA, it has several limitations. It is a passive system, and thus only a small percentage of adverse events are recorded. It is also more useful for identifying short-term overt effects (e.g., cardiac arrest associated with ephedrine-containing products) than long-term effects such as liver cancer and other chronic diseases. It is also likely that many potentially adverse events go unrecognized. For example, one reported effect of low-level exposure to microcystins is gastrointestinal (GI) disturbance (2,3,5), and GI disturbance is apparently a fairly common experience of BGA consumers [My emphasis]. 

Not having any post-marketing surveillance in place, how can StemEnhance claim to know for a fact that there are no adverse effects associated with your product? 

19. Comment and/or Question:

Even if one accepts Drapeau’s study as accurately reflecting the effects of Stem Enhance, the amounts given to the mice would translate into a dosage of 21 grams daily for a 70 kg human adult. This presents a potential toxicity problem since the DFG report “Microcystins in algae products used as food supplements” states, “An intake of up to 3 g AFA algae/day, as recommended by the manufacturers, thus may lead to a considerable exceedance of the PTDI of the WHO.” A person consuming more than two grams of supplement containing no more than 1 ug/g of microcystin will be exposed up to the maximum allowable “safe” level of microcystin. A person consuming more than that, will be exposed to potentially harmful levels. A person who consumes ten grams of supplement per day of violative supplement having 5 ug/g or more microcystin, is potentially exposed to serious chronic, if not acute liver injury.” 

Please comment on this argument. 

20. Comment and/or Question:

Furthermore, “StemEnhance is a proprietary blend of the cytoplasmic and cell wall-rich fractions of the whole plant biomass, enriched approximately fivefold in content of the LSL compared to the raw AFA biomass. (Jensen GS, et al. / Cardiovascular Revascularization Medicine 8 (2007) 189–202 191). Does StemEnhance therefore contain 5-fold the normal microcystin content of raw AFA biomass? 

As StemEnhance is promoted for use in children and adults, and even if StemEnhance only contains levels of microcystin that are within regulatory norms, since StemEnhance is enriched fivefold, does this not suggest that a 40kg individual will be receiving twice the dose of microcystin compared to an 80 kg individual, and a 20kg child up to four times the dose? (Toxicity is related to the dose/kg). 

 

Cancer

 21. Comment and/or Question:

I have read your document, “Increase in the number of circulating stem cells by StemEnhance® does not promote tumor growth” and the recent publication, Drapeau C, Ma H, Yang Z, Tang L, Hoffman RM, Schaeffer DJ. The stem cell mobilizer StemEnhance does not promote tumor growth in an orthotopic model of human breast cancer. Anticancer Res. 2009 Jan;29(1):443-7, but Christian Drapeau, the studies chief author, is the creator of Stem Enhance and it is certainly possible that he has a significant economic interest in designing and reporting studies favorable to the product. His solitary study should not be viewed outside of the context of the many studies that link bone marrow stem cells to cancer metastasis, inter alia:

Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007 Oct 4;449(7162):557-63.

Dittmer A, Hohlfeld K, Lützkendorf J, Müller LP, Dittmer J. Human mesenchymal stem cells induce E-cadherin degradation in breast carcinoma spheroids by activating ADAM10. Cell Mol Life Sci. 2009 Jul 15. 

Rhodes LV, Muir SE, Elliott S, Guillot LM, Antoon JW, Penfornis P, Tilghman SL, Salvo VA, Fonseca JP, Lacey MR, Beckman BS, McLachlan JA, Rowan BG, Pochampally R, Burow ME. Adult human mesenchymal stem cells enhance breast tumorigenesis and promote hormone independence. Breast Cancer Res Treat. 2009 Jul 12. 

Li N, Yang R, Zhang W, Dorfman H, Rao P, Gorlick R. Genetically transforming human mesenchymal stem cells to sarcomas: changes in cellular phenotype and multilineage differentiation potential. Cancer. 2009 Jul 10. 

Xiong-Zhi W, Dan C, Guang-Ru X. Bone marrow-derived cells: roles in solid tumor. Neoplasma. 2007;54(1):1-6.

“Recently, research indicated that solid tumors may originate from bone marrow stem cells. Bone marrow-derived cells have recently been shown to contribute to stromal formation, especially angiogenesis and lymphvasculogenesis.” 

Takakura, N. Role of hematopoietic lineage cells as accessory components in blood vessel formation. Cancer Sci. 2006 Jul;97(7):568-74.

“Most recently we found that hematopoietic cells play major roles in tumor angiogenesis by initiating sprouting angiogenesis and also in maturation of blood vessels in the fibrous cap of tumors.” 

Varner, JA. Stem cells and neurogenesis in tumors. Prog Exp Tumor Res. 2007;39:122-9.

“Bone-marrow-derived and tissue-resident stem cells promote repair of injured tissues by contributing to new blood vessel, muscle and nerve formation. These same stem cells may contribute to tumor growth and spread. Tumors express numerous growth factors that induce both angiogenesis and neurogenesis; these factors may also induce tissue-resident stem cell recruitment and differentiation. Tumors also recruit circulating bone-marrow-derived stem or progenitor cells, which play roles in promoting tumor growth and spread. As innervation of tumors promote cancer pain and can contribute to tumor spread, an understanding of the roles of stem cells in tumor innervation will assist in the development of new cancer therapies.” 

It is widely recognized that industry-sponsored studies overwhelmingly produce results favorable to a product while independent studies often show an unfavorable result. Could you please address the apparent contradiction between your claim of lack of potential carcinogenicity of stem cells and recent peer-reviewed publications?

 

Cancer – L-selectin ligand

 22. Comment and/or Question:

According to StemEnhance, “StemEnhance contains an L-selectin ligand, a type of compound known to trigger stem cell mobilization from the bone marrow.” 

Can StemEnhance state with certainty that supplying individuals with additional, or possibly excessive L-selectin ligand compounds, is safe and will not result in adverse effects. I refer you to the following studies which suggest that L-selectin ligands have potential adverse effects. 

Shigeta A, Matsumoto M, Tedder TF, Lowe JB, Miyasaka M, Hirata T. An L-selectin ligand distinct from P-selectin glycoprotein ligand-1 is expressed on endothelial cells and promotes neutrophil rolling in inflammation. Blood. 2008 Dec 15;112(13):4915-23. Epub 2008 Sep 25.

“These results provide evidence for the existence of an L-selectin ligand distinct from PSGL-1 in inflammation and indicate that such a ligand is expressed on endothelial cells, promoting neutrophil rolling in vivo.” 

Radhakrishnan P, Lin MF, Cheng PW. Elevated expression of L-selectin ligand in lymph node-derived human prostate cancer cells correlates with increased tumorigenicity. Glycoconj J. 2009 Jan;26(1):75-81. Epub 2008 Aug 1.

Human prostate cancer LNCaP cells including C-33 and C-81 cells were originally derived from the lymph nodes of a patient with metastatic prostate cancer. These two cells were employed for characterization of L-selectin ligand and in vitro tumorigenicity, because they mimic the clinical conditions of early and late-stage human prostate cancer. C-81 cells exhibit higher in vitro migratory and invasive properties as compared with C-33 cells. We find that the L-selectin ligand and mucin glycan-associated MECA-79 epitope were elevated in C-81 cells. An increase of these glycotopes positively correlates with elevated tumorigenicity and expression of key glycosyl- and sulfotransferase genes. These results suggest that modulated expression of selective glycogenes correlates with altered tumorigenicity of cancer cells. 

Resto VA, Burdick MM, Dagia NM, McCammon SD, Fennewald SM, Sackstein R. L-selectin-mediated lymphocyte-cancer cell interactions under low fluid shear conditions. J Biol Chem. 2008 Jun 6;283(23):15816-24. Epub 2008 Apr 1.

Cell migration in blood flow is mediated by engagement of specialized adhesion molecules that function under hemodynamic shear conditions, and many of the effectors of these adhesive interactions, such as the selectins and their ligands, are well defined. However, in contrast, our knowledge of the adhesion molecules operant under lymphatic flow conditions is incomplete. Among human malignancies, head and neck squamous cell cancer displays a marked predilection for locoregional lymph node metastasis. Based on this distinct tropism, we hypothesized that these cells express adhesion molecules that promote their binding to lymphoid tissue under lymphatic fluid shear stress. Accordingly, we investigated adhesive interactions between these and other cancer cells and the principal resident cells of lymphoid organs, lymphocytes. Parallel plate flow chamber studies under defined shear conditions, together with biochemical analyses, showed that human head and neck squamous cell cancer cells express heretofore unrecognized L-selectin ligand(s) that mediate binding to lymphocyte L-selectin at conspicuously low shear stress levels of 0.07-0.08 dynes/cm(2), consistent with lymphatic flow. The binding of head and neck squamous cancer cells to L-selectin displays canonical biochemical features, such as requirements for sialylation, sulfation, and N-glycosylation, but displays a novel operational shear threshold differing from all other L-selectin ligands, including those expressed on colon cancer and leukemic cells (e.g. HCELL). These data define a novel class of L-selectin ligands and expand the scope of function for L-selectin within circulatory systems to now include a novel activity within shear stresses characteristic of lymphatic flow. 

León B, Ardavín C. Monocyte migration to inflamed skin and lymph nodes is differentially controlled by L-selectin and PSGL-1. Blood. 2008 Mar 15;111(6):3126-30. Epub 2008 Jan 9.

Monocyte recruitment and differentiation into dendritic cells or macrophages play a critical role in defense mechanisms against pathogens and in inflammatory and autoimmune diseases. Important contributions have been made on the molecular events controlling neutrophil and lymphocyte extravasation under steady state or inflammation. However, the molecules involved in monocyte rolling during their migration to antigen capture areas and lymphoid organs during infection remain undefined. Here we have analyzed the homing molecules controlling mouse monocyte rolling in an experimental model of Leishmania major infection. Monocyte migration through inflamed dermal venules was dependent on interactions of PSGL-1 with P- and E-selectins, and of L-selectin with PNAd, whereas migration through lymph node high endothelial venules relied essentially on L-selectin-PNAd interactions. These results might have important implications regarding the induction of immune responses against pathogens and future immunotherapeutic protocols of inflammatory and autoimmune diseases, based on selective inhibition of monocyte migration to specific inflammatory foci. 

Barthel SR, Gavino JD, Descheny L, Dimitroff CJ. Targeting selectins and selectin ligands in inflammation and cancer. Expert Opin Ther Targets. 2007 Nov;11(11):1473-91.

Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Harvard Institutes of Medicine, Room 669, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

Inflammation and cancer metastasis are associated with extravasation of leukocytes or tumor cells from blood into tissue. Such movement is believed to follow a coordinated and sequential molecular cascade initiated, in part, by the three members of the selectin family of carbohydrate-binding proteins: E-selectin (CD62E), L-selectin (CD62L) and P-selectin (CD62P). E-selectin is particularly noteworthy in disease by virtue of its expression on activated endothelium and on bone-skin microvascular linings and for its role in cell rolling, cell signaling and chemotaxis. E-selectin, along with L- or P-selectin, mediates cell tethering and rolling interactions through the recognition of sialo-fucosylated Lewis carbohydrates expressed on structurally diverse protein-lipid ligands on circulating leukocytes or tumor cells. Major advances in understanding the role of E-selectin in inflammation and cancer have been advanced by experiments assaying E-selectin-mediated rolling of leukocytes and tumor cells under hydrodynamic shear flow, by clinical models of E-selectin-dependent inflammation, by mice deficient in E-selectin and by mice deficient in glycosyltransferases that regulate the binding activity of E-selectin ligands. Here, the authors elaborate on how E-selectin and its ligands may facilitate leukocyte or tumor cell recruitment in inflammatory and metastatic settings. Antagonists that target cellular interactions with E-selectin and other members of the selectin family, including neutralizing monoclonal antibodies, competitive ligand inhibitors or metabolic carbohydrate mimetics, exemplify a growing arsenal of potentially effective therapeutics in controlling inflammation and the metastatic behavior of cancer. 

 

Regulatory requirements

 23. Comment and/or Question:

You claim that StemEnhance has been registered with the South African Medicines Control Council but I have pointed out that all you have is a letter or number of receipt of documentation. Please supply evidence (i.e. a copy of the certificate of registration issued in terms of the Medicines Act and signed by the Registrar herself) to the contrary. 

24. Comment and/or Question:

StemEnhance claims not to be a medicine and at the talk given by Ms Livingston, she pointed out that users must try to avoid making these claims to avoid being “regulated by the FDA”: “get in trouble if we make medical claims – we’ll get the company in trouble. Be safe. Talk about “renewing areas of need. Don’t talk about pain, talk about discomfort.” (Recorded) It is highly misleading to talk to South African consumers about FDA regulations that do not apply in South Africa at all. Please note that in South Africa, there is not even an equivalent definition of “dietary supplement” to that in the USA.  

Stem Tech advertises “breakthrough stem cell research” but a closer look reveals that they are not selling stem cells but rather just another nutritional supplement cocktail. They claim their supplements will “help to support the release of stem cells from the bone marrow into the bloodstream.” This is the type of ambiguous “structure function” claim that the law (in the US) currently allows manufacturers to make for supplements without any requirement for research or data to back up the claims. 

Yet the South African Medicine act is very precise, and states:

For ALL products making therapeutic claims, the Medicines Act applies. The definition of a medicine according to the Act is: ‘medicine’ means any substance or mixture of substances used or purporting to be suitable for use or manufactured or sold for use in- (a) the diagnosis, treatment, mitigation, modification or prevention of disease, abnormal physical or mental state or the symptoms thereof in man; or (b) restoring, correcting or modifying any somatic or psychic or organic function in man, and includes any veterinary medicine;”

The home page of the MCC (www.mccza.com) states about the Medicines Act (accessed 15/11/2008): All medicines for human use are subject to this law, including complementary and complementary biological medicines. Further, all veterinary medicines must be registered in terms of the Act excluding stock remedies registered in terms of Act 36. 

Why does point (b) not apply to StemEnhance’s claims? 

25. Comment and/or Question:

a.) Ms Livingston stated words to the effect that “stress results in an increased need for stem cells, ‘a natural renewal product’ and she implied that this need could be met by taking StemEnhance”. Please supply credible scientifically published evidence to confirm that this statement is true, and that StemEnhance itself has proved to be beneficial for this condition (not by inference, or through embryonic stem cell research evidence). Indeed, in Frenette 2000 it is stated: “Circulating hematopoietic progenitor cells (HPCs) were first observed several decades ago,1,2 and it was subsequently shown that the number of circulating HPCs could be augmented by chemotherapy, endotoxin administration, or stress.”Frenette PS, Weiss L. Sulfated glycans induce rapid hematopoietic progenitor cell mobilization: evidence for selectin-dependent and independent mechanisms. Blood. 2000 Oct 1;96(7):2460-8. 

b) How is Ms Livingston’s claim not in conflict with (b) in the previous question? (i.e. how is it not “purporting to be suitable for use” in stress, when her very words state the opposite?

26. Comment and/or Question:

The contents of the email below was sent out by your distributors. The fact that two distributors sent out the same message, and similar messages are made by other StemTech distributors on the internet, suggests that StemTech has evidence to support the claims being made. 

“Discoveries in stem cell research point to novel concept behind the formation of diseases.  A well known fact is that every couple of years we have a totally new body.   The truth of the matter is that this turnover time is almost impossible to determine and it varies from organ to organ.  But the principle remains true. Whereas the lining of the intestine renews itself every 5 days or so, the liver renews itself every 2 years, and the lung every 4 years or so even the brain would renew itself every 20-30 years. What is important to understand is that if the body loses cells at such a rate, in order to remain healthy and functional, the body must renew itself at the same rate, How:  it is the role of the stem cells from your bone marrow to travel and do the day-to-day replacement of cells that are lost daily, ensuring the maintenance of optimal health Due to an imbalance between degeneration and stem cell-based regeneration disease develops; if cells can renew faster than they are lost, health ensues. Eg.  If cells of the pancreas die faster than they can renew, diabetes slowly develops.  If cells of the brain are lost faster than they can renew, e.g. Parkinson or Alzheimers develop. If stem cells can travel and renew these organs at a rate equal or faster than cell death, health is maintained. This information is bringing forth a new understanding of the process of disease formation.  Until now, the main approach to health was to take antioxidants or vitamins in order to prevent various diseases, or to use various drugs and therapies to treat diseases after being diagnosed.  Stem cells research point to a totally new means to maintain health that consists in supporting the stem cell based process of cellular renewal.  For example, by increasing the number of circulating stem cells, more stem cells are available to travel to the liver, pancreas, brain, heart, and other organs, contributing to disease prevention. The good news is that there is a natural safe way to increase the number of circulating stem cells from jour own bone marrow. StemEnance consists of compounds that is extracted from a natural aqua botanical called AFA. It increases the number of circulating stems cells by 25% within an hour of consumption. Even though the product is not intended  to cure prevent or diagnose any illness or disease, numerous positive personal testimonies have been received from people that suffered from * Respiratory disease: Asthma, Emphysema

* Joint disease: Arthritis Gout

* Neurological disorders: Parkinsons Altzheimers, damage as a result of Stroke

* Skeletal disease: Osteoporosis, hips  knees

* Heart and Pancreas: Diabetes recovery from heart attack,

* Auto Immune Conditions: Multiple Sclerosis

If you would like more info on StemEnhance please do not hesitate to contact me. 

Martie Grobler 

Please supply credible scientific, peer-reviewed articles demonstrating that StemEnhance itself, and not by inference, has been shown to be effective in these conditions. 

27. Comment and/or Question:

Ms Livingston asks that distributors not claim that StemEnhance causes healing or regeneration, but that StemEnhance results in “renewal”. What is the difference between these claims and how is the word “renewal” not in conflict with point (b) of the South African Medicines Act, as stated above. (I.e. purporting to be suitable for use in “renewal”?) 

 

StemFlo

 28. Comment and/or Question:

StemFlo is claimed to “support optimal circulation of stem cells throughout out the entire body” and this is deduced or “inferred” by cherry picking of individual studies to support a claim being made for the individual ingredients. Please supply peer-reviewed studies that either confirm the claims being made by StemFlo based on actual research of StemFlo’s ability to support optimal circulation of stem cells, and/or that the individual ingredients are not antagonistic. Please show that the mix does not invalidate the individual claims of the individual ingredients. 

29. Comment and/or Question:

Natural Medicines Comprehensive Database, the “Scientific Gold Standard for Evidence-Based, Clinical Information on Natural Medicines”, a very credible and central reference for reviews of natural medicines, finds no efficacy for the claims being made for the ingredients, mangosteen, cat’s claw extract (Uncaria guianensis), turmeric, Rehmannia glutinosa, etc, used in StemFlo. 

Why should users believe your cherry-picked studies, done many only on rats or mice, as opposed to a proper review of the efficacy of the individual ingredients on humans and conducted by highly respected scientists?

 

Miscellaneous

 30. Comment and/or Question:

Much is made about StemEnhance having a patent, and by implication that the product therefore has efficacy. 

Does a patent always indicate proof of a product’s benefit or proof of efficacy? 

31. Comment and/or Question:

The World Health Organisation and all international scientific groups have developed guidelines for grading the quality of evidence and the strength of recommendations used for evaluating a study. Can you name any of the grading systems that have been applied to the scientific evidence for StemEnhance, what the grading level was, and if not applied, why not. 

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    […] to the chief scientist, Mr Christian Drapeau, who would adequately address my concerns. Fourteen pages of questions concerning StemEnhance was sent to Mr Drapeau for his […]

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