In 1994, before leaving the UK for the Pacific Northwest, I published a paper in the European Journal of Herbal Medicine on how herbalists could benefit from the internet for research, communication and community. At that time most European herbalists did not have email; 14.4k dialup was fast, my computer was an Apple SE30, the infant web was accessed through Mosaic and the late Professor Farnsworth’s pharmacognosy database NAPRALERT required telnet access and returned reams of ASCI text on a dot matrix printer after a herbal query.  In the same year,  I founded Herbal Hall with  two West coast US herbal colleagues -  a professional herbalist bulletin board - pioneering the use internet as a tool for  herbalists to share knowledge and information.  Since then a lot of bits and bytes have passed through the ether. I am writing this post on an iPAd, not only have Steve Jobs and Norman Farnsworth  both left us, but herbalists too have passed; in 2003 William Le Sassier, in 2009 Michael Moore. We stand on the shoulders of giants.

This site, Herbological.com was set up in 2000, and includes Herbal Bookworm, as well as some concept articles under the rubric of Herbal Hypotheses. The site was revamped in 2005 with the launch of the original Herblog - which you are reading now.  After 3 years, as the blogosphere developed, web 2.0 matured, and the challenges of publishing a major medical text on herb-drug interactions while maintaining a full time clinical practice began to limit time available for my blogging: it became clear that a more focused approach was called for.  Despite hundreds of thousands of page views, downloads and a significant “impact factor” (or notoriety), herbological.com and herblog were not updated after 2008.  Shortly they will cease to exist.

Herblog 2  will focus on specifically on botanical medicine  and cancer, and herb-drug interactions. Through these two prime lenses, the emerging features of what I call Herbalism 3.0 will become clarified, developed and discussed. The plan is that this tighter focus will make Herblog 2 a unique resource for healthcare professionals, herbalists and cancer patients seeking reliable information on herbal medicine for the coming era. Check back soon!

Bakrim, A., A. Maria, et al. (2008). “Ecdysteroids in spinach (Spinacia oleracea L.): Biosynthesis, transport and regulation of levels.” Plant Physiology and Biochemistry 46(10): 844-854.

Many plant species produce phytoecdysteroids (PEs: i.e. analogues of insect steroid hormones). There is increasing evidence that PEs are used as a chemical defence by plants against non-adapted insects and nematodes. PEs are good candidates for the development of an environmentally safe approach to crop protection. Most crop species do not accumulate PEs. However, many arguments support the idea that most, if not all, plant species have the genetic ability to produce PEs, but the biosynthetic pathway is not active. A better understanding of the PE biosynthetic pathway and its regulation is consequently necessary. Spinach is one of the very few crop plants which produce large amounts of PEs, of which 20-hydroxyecdysone is the major component. Labeling experiments with radiolabeled precursor (mevalonic acid), putative ecdysteroid intermediates and 20-hydroxyecdysone itself have allowed investigation of PE biosynthesis and transport during spinach development. Biosynthesis takes place in older leaf sets (”sources”), but not in the young developing ones, which in contrast accumulate (acting as “sinks”) the PEs produced by the older leaves. PEs are thus continuously redistributed within the developing plant, as its leaf set number increases. The biosynthetic pathway has been analyzed using excised leaves and various labeled precursors, and a preferential sequence of the last steps has been established. Although they do not produce PEs, apical leaf sets are nevertheless able to perform several putative terminal steps of PE biosynthesis. The regulatory mechanisms of PE synthesis appear to involve a direct negative feedback of 20-hydroxyecdysone (the major PE in spinach) on its own synthesis; thus, a sustained synthesis in older leaves requires that they can export the PE they produce.

Write to Sue Evans in Australia and ask her for a pdf of this recent paper, based on her doctoral thesis. Its important.

sue.evans@scu.edu.au

Changing the knowledge base in Western herbal medicine.:

Soc Sci Med. 2008 Oct 25;

Authors: Evans S

The project of modernising Western herbal medicine in order to allow it to be accepted by the public and to contribute to contemporary healthcare is now over two decades old. One aspect of this project involves changes to the ways knowledge about medicinal plants is presented. This paper contrasts the models of Evidence-Based Medicine (EBM) and Traditional Knowledge (TK) to illuminate some of the complexities which have arisen consequent to these changes, particularly with regard to the concept of vitalism, the retention or rejection of which may have broad implications for the clinical practice of herbal medicine. Illustrations from two herbals (central texts on the medicinal use of plants) demonstrate the differences between these frameworks in regard to how herbs are understood. Further, a review of articles on herbal therapeutics published in the Australian Journal of Herbal Medicine indicates that practitioners are moving away from TK and towards the use of EBM in their clinical discussions.

PMID: 18952343 [PubMed - as supplied by publisher]

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This is interesting - a week to get from SJW induction of 3A4 to return to steady state pre-induction levels of a 3A4 substrate. It suggests that week-on / week-off pulsing is a good bet for “tricking” the hepatic mixed oxidase system into maintaining steady levels of a 3A4 substrate in the setting of induction - for example artemsinin which induces its own clearance.

The recovery time-course of CYP3A after induction by St John’s wort administration.

Br J Clin Pharmacol. 2008 May;65(5):701-7

Authors: Imai H, Kotegawa T, Tsutsumi K, Morimoto T, Eshima N, Nakano S, Ohashi K

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: St John’s wort causes the induction of CYP3A. Little is known about how long the effect remains after cessation of St John’s wort. WHAT THIS STUDY ADDS: The in vivo CYP3A activity returns progressively to the basal level approximately 1 week after cessation of St John’s wort administration AIMS: To examine the recovery time course of CYP3A after enzyme induction by St John’s wort administration. METHODS: The subjects were 12 healthy men, aged 20-33 years. On the first day, they received an oral dose of midazolam 5 mg without St John’s wort (day -14). From the next day, they took St John’s wort for 14 days. On the last day of St John’s wort treatment (day 0) and 3 and 7 days after completion of St John’s wort treatment (days 3 and 7), they received the same dose of midazolam. On each day, blood samples were obtained until 8 h after midazolam administration. Plasma concentrations of midazolam were measured by HPLC. Pharmacokinetic parameters of midazolam were determined using noncompartmental analysis. RESULTS: Apparent oral clearance of midazolam was significantly increased after St John’s wort administration from 65.3 +/- 8.4 l h(-1) (day -14) to 86.8 +/- 17.3 l h(-1) (day 0). It returned to the control level 7 days after the completion of St John’s wort (day 7, 59.7 +/- 3.8 l h(-1)). No significant difference in the elimination half-life between the four periods of the study was observed. The changes in apparent oral clearance after St John’s wort discontinuation indicated that CYP3A activity recovers from enzyme induction with an estimated half-life of 46.2 h. CONCLUSIONS: CYP3A activity induced by St John’s wort administration progressively returns to the basal level after approximately 1 week. This finding may provide useful information to avoid clinically significant interactions of St John’s wort with CYP3A substrates.

PMID: 18294328 [PubMed - indexed for MEDLINE]

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The same flavonoid reported in the last post, this time extracted from Smilax, inhibiting cervical cancer cell line HeLa.

Kaempferol-7-O-beta-D-glucoside (KG) isolated from Smilax china L. rhizome induces G2/M phase arrest and apoptosis on HeLa cells in a p53-independent manner.:

Cancer Lett. 2008 Jun 18;264(2):229-40

Authors: Xu W, Liu J, Li C, Wu HZ, Liu YW

Kaempferol-7-O-beta-D-glucoside (KG), a flavonoid glycoside, isolated from Smilax china L. rhizome, displayed marked anticancer activity on a panel of established cancer cells, of which, HeLa human cervix carcinoma cells were the most sensitive. Meanwhile, the cytotoxic effects of KG on normal human cells (HEK293 embryonic kidney cells and L-02 embryonic liver cells) were much smaller than on cancer cells. This work studied the molecular mechanisms underlying KG induced growth inhibition in HeLa cells. The results showed that KG induced G2/M phase growth arrest correlated with Cyclin B1 and Cdk1 decrease in a p53-independent manner, and also caused an increase in apoptosis, which was confirmed by characteristic morphological changes, evident DNA fragmentation, increased apoptotic sub-G1 population. Furthermore, inhibition of NF-kappaB nuclear translocation, up-regulation of Bax and down-regulation of Bcl-2, were observed in HeLa cells treated with KG, which indicated that the mitochondrial pathway was involved in the apoptosis signal pathway. In summary, KG displayed a significant anti-tumor effect through cell cycle arrest and apoptotic induction in HeLa cells, which suggested that KG might have therapeutic potential against cervix carcinoma.

PMID: 18343026 [PubMed - indexed for MEDLINE]

Another study demonstrating the the anticancer properties of ginkgo and its constituents - now with pancreatic cancer.

Ginkgo biloba extract kaempferol inhibits cell proliferation and induces apoptosis in pancreatic cancer cells.

J Surg Res. 2008 Jul;148(1):17-23

Authors: Zhang Y, Chen AY, Li M, Chen C, Yao Q

BACKGROUND: Kaempferol is one of the most important constituents in ginkgo flavonoids. Recent studies indicate kaempferol may have antitumor activities. The objective of this study was to determine the effect and mechanisms of kaempferol on pancreatic cancer cell proliferation and apoptosis. MATERIALS AND METHODS: Pancreatic cancer cell lines MIA PaCa-2 and Panc-1 were treated with kaempferol, and the inhibitory effects of kaempferol on pancreatic cancer cell proliferation were examined by direct cell counting, 3H-thymidine incorporation, and MTS assay. Lactate dehydrogenase release from cells was determined as an index of cytotoxicity. Apoptosis was analyzed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay. RESULTS: Upon the treatment with 70 microm kaempferol for 4 days, MIA PaCa-2 cell proliferation was significantly inhibited by 79% and 45.7% as determined by direct cell counting and MTS assay, respectively, compared with control cells (P < 0.05). Similarly, the treatment with kaempferol significantly inhibited Panc-1 cell proliferation. Kaempferol treatment also significantly reduced 3H-thymidine incorporation in both MIA PaCa-2 and Panc-1 cells. Combination treatment of low concentrations of kaempferol and 5-fluorouracil showed an additive effect on the inhibition of MIA PaCa-2 cell proliferation. Furthermore, kaempferol had significantly less cytotoxicity than 5-fluorouracil in normal human pancreatic ductal epithelial cells (P = 0.029). In both MIA PaCa-2 and Panc-1 cells, apoptotic cell population was increased when treated with kaempferol in a concentration-dependent manner. CONCLUSIONS: Ginkgo biloba extract kaempferol effectively inhibits pancreatic cancer cell proliferation and induces cancer cell apoptosis, which may sensitize pancreatic tumor cells to chemotherapy. Kaempferol may have clinical applications as adjuvant therapy in the treatment of pancreatic cancer.

PMID: 18570926 [PubMed - indexed for MEDLINE]

The Weber-headed study by Bastyr, using NCCAM money and featuring Harvard Pharma pimp Biederman used an ineffective product to treat a so-called condition for which no practitioner in their right mind would ever use the herb, based on a completely hokey survey by some pharmacists in Texas that found 5 kids had been prescribed SJW for depression or ADHD.

One of the phenomena of the mainstream misinformation machine regarding herbal medicine is that any study, especially one published in JAMA, is apparently endowed with an aura of truth as if it were directly received from above on tablets of stone. This completely worthless and near fraudulent study of course failed to detect anything of consequence. But as a result the PR machine of mainstream news generation went straight into action, internet and press headlines proclaiming that St John’s Wort does not work for ADHD.

Mike Adams, an investigative reporter for Natural News Magazine in his expose of the Bastyr/ADHD/Hypericum study compiled a list of such headlines.

St. John’s wort fails to help kids with ADHD
The Associated Press

St. John’s Wort Doesn’t Work for ADHD
Washington Post

St. John’s Wort No Help in ADHD
ABC News

St. John’s wort no better than placebo for ADHD, Bastyr study finds
Seattle Times

St. John’s Wort No Help for ADHD
TIME Magazine

Herb does not ease ADHD
ZDNet

St. John’s wort doesn’t help ADHD, study finds
Reuters

None of which should surprise regular readers of HERBLOG, and none of which should surprise Bastyr. Hopefully the Bastyr Board will look at this pile of stinking stuff and ask Weber at al some hard questions. Promoting an understanding of how to use of herbal medicine in the modern world requires a little more than brown-nosing Big Pharma, validating DSM IV, and collaborating with corrupt truth twisters with an agenda to promote chemical control of kids behavior. This study does all of this and more.

HERBLOG awards this appalling study the title of jackass trial of the year. Let us hope that the good people at Bastyr wake up and do some genuine soul-searching.
This kind of thing does them no good at all.

Time to move on.

Biederman’s career highlights include a series of clinical trials to “prove” the efficacy of the ADHD drug atomoxetine (Strattera). Unlike Ritalin, this is not a direct stimulant, but appears to function as a norepinephrine reuptake inhibitor. (indirect stimulant for FWIW) The drug is made by Ely Lilly, one of Biederman’s major undisclosed sponsors (see earlier HERBLOG post about his failure to truthfully disclose conflict of interest payments.)

As discussed in the last HERBLOG post, the author’s justification for this clinical trial included the absurd claim that because 5 kids in Texas might have taken SJW for ADHD or depression, that Hypericum is the most prescribed herb for this “condition” of ADHD in the whole of the USA. On the same topic - ( ie Why the F***? ) there is yet another preposterous claim in the paper. In the introduction to the study, the authors state that …“since the NE uptake inhibitor atomoxetine has been approved by the FDA for ADHD and because Hypericum is believed to act as a norepinephrine reuptake inhibitor, we hypothesized that it may be beneficial in the treatment of ADHD….”

This so-called hypothesis is unmitigated nonsense.

Hypericum is NOT a NE reuptake inhibitor. That term refers to the pharmacological action of a drug (such as atomoxetine). Hypericum is a mild herb. Mild herbs are not drugs. They do not display drug type magic bullet actions. Hallo - Bastyr…come in please…where are you???? Do we really have to go through the fact that SJW is not a NERI, not an MAOI, not an SSRI, not even all of the above….

But for Biederman and Ely Lilly to be able to say that the Hypericum or any herb for that matter, does not work for ADHD…is to say the least convenient, if somewhat marginal. Sounds like a bit of a set up? Sounds like Bastyr folk walked right into it too. Nothing like an Institution that teaches botanical medicine saying that a her b does not work..it really must mean it does not work. Maybe they did not see the headlines coming….what headlines?

What headlines?….See next post.

One of the original  questions posed about this whole fiasco of a study is why on earth would a progressive-thinking center of excellence in natural medicine even contemplate trialling any medicine for so called ADHD?  Labels such as ADHD are arguably fictive (or philosophically nominalist) descriptors that do not refer to a real entity at all.  The DSM manual which taxonomically lists these “psychiatric disorders” can be seen as an elaborate hoax to support Big Pharma and psychopharmaceutical behavior control. Let us not forget that this is the same “authority” that labelled homosexuality as a “psychiatric disease” only a few years back. The whole business of mass-medicating children with psychotropic drugs is objectionable, and If there is a genuine question around herbal/botanical  interventions for children expressing the kind of behavior labelled ADD/ADHD  then the question comes up why SJW or Hypericum in the first place? There seems to be no rationale in traditional herbal prescribing for using SJW to influence this kind of behavior. SJW is a woundwort or healing herb, a liver herb, with a recent “biomedical” reputation for efficacy in certains forms of depression, although the trial data for this indicationis varying in quality and quantity. However, it is very improbable that any  trained practitioner, let alone licensed ND would propose taking SJW for ADHD. EVen the popular/consumer level  “natural” remedies given for so called ADHD generally include  either “stimulants” such as caffeine, and calming herbs such as Valerian, Kava and Scutellaria. SJW? not really.The rationale given in the Bastyr/JAMA paper for performing this clinical trial is that SJW is the most common herbal treatment for children with ADHD in the US. (along with Echinacea and Ginkgo). And where does this strange piece of information come from? The answer in the text is the citing of a reference to a questionnaire by three pharmacists  which surveyed a small number of caregivers  or parents of children attending community mental health centerers in urban, suburban and rural Texas. We have obtained the full text of this tedious little paper (see link below) . While the authors of the survey were probably well-intentioned, the document’s import is laughable when compared to the claims made for its significance by the Bastyr study authors. Firstly the children were diagnosed with EITHER depression or ADHD. Of 117 total patients, 5 (five) out of  n=117 who had either depression or ADHD had been given some SJW. A couple more were given Echinacea and or Ginkgo. From this entirely irrelevant and meaningless exercise we somehow get from 5 kids in Texas with depressive/ADHD diagnoses being given SJW on a one time basis  to the absurd and ludicrous claim that Hypericum is the most common herbal treatment for pediatric ADHD in the United States. This is extrapolation is bogus science masquerading as authoritative information - gone compeletely beserk. I was goingto make a cultural comment about the iPod being invented in Cupertino not Waco, but this stuff is not even remotely funny.Cala S, Crismon ML, Baumgartner J.Pharmacotherapy. 2003 Feb;23(2):222-30. A survey of herbal use in children with attention-deficit-hyperactivity disorder or depression.This is not the end of the study’s flimsy self-justification however attempts; the next reason given for performing this study is based  on erroneous  statements about the psychopharmacology of Hypericum. Stay tuned. We have started so we will finish.

According to the full text The Bastyr Hypericum/ADHD trial used a SJW product supplied by Vital Nutrients Inc that is “marketed as standardized to 0.3% hypericin”. The text further relates this material was “independently” verified prior to the trial, and also suggests that the extract was not a high hyperforin ( 3-5%) type of product. This is part of the end discussion in the paper that suggested the effects being tested were a result of hypericin not hyperforin.

An interesting point emerges here: Vital Nutrients Inc is a reputable company run by Bastyr alum Dr Rik Liva. Liva has established a solid reputation in the natural products industry as a vigorous proponent of GMPs, quality assurance and the need for testing to ensure quality in dietary supplements. He has often gone on public record as saying that adherence to QA/GMPs is absolutely necessary to prevent the public from being duped. But when his owncompany’s extract was tested it was found to be 0.13% hypericin not 0.3% as labelled. This is a huge discrepancy. Perhaps the “independent” testing of the initial material was simply a wholesale suppliers “C of A (Certificate of Assurance) about the quality? A further puzzle is that Vital Nutrients do not actually market a “low hyperforin” SJW product. Their web site lists only a 3-5% hyperforin SJW item

SO it could be said that Liva’s Vital Inc producthad the potential for duping the consumer, it duped the triallists at any rate. The abstract could easily have read something like “egg on face as clinical trial fails to measure anything due to clusterfuck confusion over product administered to verum group” but then that would not have made the study authors or their Bastyr alum’s company look too clever.

Since Liva is pretty adept at publicity, perhaps we will be hearing from him about the apparent problems with the product used in the trial. Perhaps the “independent verification” of the supplied material could be revealed? The Bastyr paper itself suggests that the product probably became oxidized during the 8 week trial due to its being dispensed in 2- part capsules. One would hope for a longer than 8 week shelf life for most products….Perhaps Liva will shortly be reoutfitting the Vital Nutrients SJW in a “onezie” suit.

To be continued..