In a final desperate attempt to justify the claim that swimming man died from a ginkgo-interaction induced breakthrough seizure, Kupiec and Raj launch into a discussion of possible pharmacokinetic interactions caused by ginkgo modulation of the phase 1 or mixed oxidase drug metabolizing system. Unfortunately, they rapidly find themselves out of their depth.

Some HERBLOG readers may not want to bother with these details, but for the hardcore here goes: both valproate and phenytoin undergo complex metabolic transformation. Suffice it to say that phenytoin is a substrate of cytochromes 2C9, 2C19, 2E1 and at the same time induces 3A4, 2C9, 2C19 and 1A2. Valproate is a substrate of 2C9, 2C19, 2A6, and may also inhibit 2C9, 2C19 and phase 2 enzymes. Clearly co-administration of these drugs is likely unpredictable, especially when the fact is taken into account that both 2C9 and 2C19 have polymorphisms (poor and extensive metabolising variants). The effect of these polymorphisms on epileptic patients on response variability has been been documented, (but this is not reported by the authors) and is also a likely explanation for the well known occurrence of breakthrough seizures in the drug combination.

The principal metabolizing enzyme for both drugs however is 2C9. The effect of ginkgo administration on human 2C9 has been studied in vivo and … there is no effect. Here is the key paper:

Mohutsky, M. A., G. D. Anderson, et al. (2006). “Ginkgo biloba: Evaluation of CYP2C9 Drug Interactions In Vitro and In Vivo.” Am J Ther 13(1): 24-31.

Ginkgo biloba extract is one of the most widely used herbal products in the United States. However, bleeding episodes in patients taking Ginkgo biloba and warfarin have been documented. Therefore, in vitro and in vivo inhibition studies were done to ascertain the influence of ginkgo on CYP2C9, the P-450 isozyme responsible for the metabolism of the most potent warfarin enantiomer, (S)-warfarin. Ginkgo extract inhibited human liver microsomal CYP2C9 with an apparent Ki =14.8 mug/mL, and the inhibition was increased by acid hydrolysis (apparent Ki = 9.1 mug/mL). Two open-label, crossover pharmacokinetic studies in healthy subjects were performed using tolbutamide and diclofenac as probe CYP2C9 substrates. In contrast to the in vitro inhibition of CYP2C9, no interactions between Ginkgo biloba extract and CYP2C9 probe substrates were observed in vivo as evidenced by the lack of effect on the steady-state pharmacokinetics of diclofenac or on the urinary metabolic ratio of tolbutamide.

In other words, the mechanism proposed by the authors of the swimming man report is in conflict with the only available evidence. Undeterred, our authors quote a study on prilosec metabolism being affected by ginkgo. Prilosec of course is metabloized by 2C19 not 2C9. Once again, the authors attempt to imply that research supports their claim, when in fact the opposite is the case. How bad can this get?
The main question is rapidly becoming will the swimming man case report become inducted into the mainstream misinformation hall of shame? Check back soon for the grand finale…

IN the “discussion” section of their misinformation case report alleging fatal seizures caused by ginkgo, Kupiec and Raj implicate the existence of a neurotoxic compound in the plant. This compound, 4′-O-methoxypyridoxine (4MPN) occurs in ginkgo nuts.

In Asian medicine, ginkgo seed (nut) or Bai Guo is a separate remedy from the leaf. Bai Guo is considered a lung remedy for dispelling phlegm, it also helps with incontinence and leukorrhea. The nuts have a mild toxicity and are often dry fried to prepare them for medicinal use - this lowers the toxicity. Overdoses of nuts have been reported in China and Japan, these are all cases of inadvertent poisoning, (rather like kids eating oleander fruit here) at a level of 70-150 seeds in children and 40-300 nuts in adults. A range of neurological symptoms follow from overdose of ginkgo nuts, including seizures, and in severe cases fatalaties have been reported if emergency care was not available following intoxication. No cases of ginkgo nut intoxication have ever been reported in the West, and the nut is not used in western herbal medicine at all.
For pharmacologically minded HERBLOG readers, 4MPN is present in nuts at a level of ~80 micrograms per nut. The same compound has been found in minute trace quantities in leaf, ranging from 1 microgram up to 5 micrograms per leaf in some instances. In toxicology studies oral LD50 of 4MPN in guinea pigs is 11 mg/Kg which results in death by convulsions and ventricular fibrillation. In other words for an 80 Kilo adult about a gram of 4MPN would be a potentially lethal dose. The typical exposure that would follow from standardized ginkgo leaf extract as used in herbal medicine would be around 10 micrograms per day, possibly a little more if the leaf had unusually high levels of this trace compound. (For references see the AHP monograph for Ginkgo). 10 micrograms is therefore approximately 5 orders of magnitude lower than a possible toxic dose likely to induce a fatal seizure in humans, as far as one can tell from the available data. Hardly a plausible bet for killing off swimming man, who it must be remembered has not actually been confirmed as consuming any ginkgo leaf extract at all, and who was certainly not involved in consumption of ginkgo nuts.

However, none of this restrains the enthusiasm of the authors of this report in their attempts to link seizures to ginkgo consumption. Boldly going where none have been before, they do not for a minute consider that ginkgo leaf is the single most prescribed and safest herbal medicine in the world or that ginkgo nut is unavailable in the West.  Despite tens of millions of doses of GBE 761 extract being sold every year, there has not been a single confirmed case of a convulsion or seizure due to ginkgo leaf, let alone a fatal episode. Adverse effects - most common are GI disturbances - run at about one per 100,000 administrations.

With this half-baked discussion of ginkgo nut toxicity, the authors (and journal editors)  simultaneously illustrate their total ignorance about herbal medicines in general and ginkgo in particular, while revealing an underlying agenda of anti-herb propaganda by means of totallly unjustified pseudoscientific claims about one of the safest remedies in the modern materia medica.

We ain’t done yet though. After the balls about nuts, the authors proceed undaunted on to the subject of ginkgo pharmacokinetics - apparently another likely explanation for the demise of swimming man. Buckle up saddle pals…we will have to deal with herbal pharmacokinetics next…stay tuned.

Our deceased swimming man ( see post of Jan 25th) had, one year prior to his fatal outing, apparently developed a seizure disorder after coronary bypass surgery which had led to a CVA (cerebrovascular accident) ie part of his brain had become damaged by the medical intervention and this, as is common, became a focus for development of seizures. Medical records indicate that prior to this he had been in “good health”. The medical chart indicates that he had taken Dilantin (phenytoin) and Depakote (valproate) - these are two standard antiseizure drugs for a year before his death. The authors of the report reproduce his serum Dilantin levels to show that they varied widely over that fatal year, three times becoming sub-therapeutic. Apparently he had also experienced a breakthrough seizure, while on the drugs, but when checked, the serum Dilantin had been at therapeutic levels during this episode. In any event, at the poolside and in the ambulance the swimming man was in v-fib (ie having a terminal heart attack, not having a seizure.) When an autopsy was later performed, the tox screen indicated subtherapeutic levels of both antiseizure meds. The cause of death was ruled to be a seizure disorder due to an old cerebrovascular event.

During this one year period from his heart surgery until his death the authors of the report allege without substantiation he had been taking “copious non-prescription (sic) vitamins, supplements, and herbal nutriceuticals”. As mentioned before there was no validated identification of any herb by binomial name, plant part, form, dose, length of administration etc at all. We are left to assume that the authors consider the variations in one year’s lab values of the drug Dilantin were due to this onslaught of unknown vitamins and herbs, which ultimately caused his death.
But a curious point emerges from the charted Dilantin levels. The date of the serum Dilantin lab levels are all from the year 2000! The date of the report is 2005, although it actually appeared in early 2006. SIX years ago???

Why have these authors waited five years to publish their allegations about so called fatal herb-drug interactions? Could it be that they are jumping on the proliferating bandwagon of anti-herb, anti-supplement misinformation, knowing that their sensational report would get them “cited by” endless secondary reviewers. Why ever would one think such a thing?

Well let’s look at the “science” proposed by the authors to support their argument…perhaps they really have a point, at least in theory, to support their allegations…stay tuned for more on the bogus science tour…

Second part, completing podcast from AHG Symposium 2000 on cardiac herbs, chaos and physiology. (33.1 MB)
Physiology + paradigm part 2.MP3

The first thing to note about this case report is the Pythonesque title:

“Fatal seizures due to potential herb-drug interactions with Ginkgo Biloba”

For the editors of this journal, literacy and logic clearly take second place to the job of insinuating a dramatic sounding anti-herb headline into the TITLE field of MEDLINE which will automatically be retrieved by others searching for ginkgo interactions. (see Herbal Hypotheses 2 for an explanation of this device) The report concerns a single patient. How many fatal seizures can a chap have? From the usual scientific perspective, (teleology excepted) the majority of effects follow from their cause. Potential events are those that have a finite probability of happening but have not happened yet. So this fatal effect apparently preceded the occurrence of its alleged cause ( a potential interaction) At least ginkgo is spelled correctly, although “Biloba” should have a small “b”since it is a proper Latin binomial.

Reading the text, we find that no-one saw the patient have a seizure at all. He was swimming in pool and was spotted by the lifeguard after becoming motionless. He was hauled out and given CPR. No sign of a seizure. Rushed to the ER, he was pronounced DOA. Autopsy revealed extensive coronary artery disease and an old cerebral infarct. What seizure?
The authors allege that the patient had been taking “copious vitamins, supplements and herbal nutriceuticals, apparently without the knowledge of his physician”. These materials were not identified. It was suggested, without any reasons being supplied , that these may have included Ginkgo leaf extracts, ginseng and saw palmetto among other things; this was not corroborated, nor was any dose, form, or product identified at all. We do not actually have a clue what they guy had taken when, why or for how long.
So far, so good, pretty much par for the course…no seizure, and no ginkgo. What about the rest of the article? What potential herb-drug interaction? Why ginkgo? Check back soon for the next episode in how to manufacture misinformation about herbal medicine using MEDLINE…

The NYT reports today how The Journal of Cell Biology is leading exposure of the issue of image manipulation as an aspect of the problem of falsification of data in scientific journals. Herbal digital wizards and Photoshop CS2 buffs should check out the full text JCB article with great pics illustrating detection of image falsification in microscopic and chromatography images by Rossner and Yamada “What’s In a Picture? The Temptation of Image Manipulation” in JCB 2004 Vol 166, (1) pp11-15

HERBLOG visitors who have read Herbal Hypotheses 2 will not be surprised to read the title of this newly published case report:

Kupiec, T. and V. Raj (2005). “Fatal seizures due to potential herb-drug interactions with Ginkgo biloba.” J Anal Toxicol 29(7): 755-8.

Alternative therapy including herbal drugs and complementary medicine is becoming increasingly popular. However, the rise in the incidence of herb-drug interactions is causing concern, especially in the absence of warning labels addressing potential adverse effects. We present the case of a 55-year-old male who suffered a fatal breakthrough seizure, with no evidence of non-compliance with his anticonvulsant medications. The autopsy report revealed subtherapeutic serum levels for both anticonvulsants Depakote and Dilantin. Concomitant with his prescribed medications, the decedent was also self-medicating with a cornucopia of herbal supplements and nutraceuticals, prominent among which was Ginkgo biloba. Ginkgo, an herbal extract from the leaves of the Ginkgo biloba tree, has been used medicinally for centuries and has been touted as a cure for a variety of medical conditions. The induction of Cytochrome P450 enzymes by components of herbal drugs has been known to affect the metabolism of various drugs. Dilantin is primarily metabolized by CYP2C9, and secondarily metabolized by CYP2C19. Valproate metabolism is also modulated in part by CYP2C9 and CYP2C19. A recent study revealed significant inductive effect of ginkgo on CYP2C19 activity. CYP2C19 induction by ginkgo could be a plausible explanation for the subtherapeutic levels of Dilantin and Depakote. Additionally, ginkgo nuts contain a potent neurotoxin, which is known to induce seizure activity. Evidence of other herbal drugs diminishing the efficacy of anticonvulsant medication does exist; however, there has been only one other documented instance of ginkgo potentiating seizure activity in the presence of anticonvulsant therapy. Highlighting the potential adverse effects and drug interactions of ginkgo on the packaging of the drug may help prevent inadvertent use in vulnerable individuals.

PUBMED

STAY tuned to HERBLOG this week for a critcal review of this report; yet another example of Mainstream Misinformation - meanwhile wait for the gutter press to pick up the feed on this “story”.

Part 1 of a 90 minute talk about physiology as the scientific foundation of western herbal medicine: but mainstream physiology must first be exorcised of concepts and terms historically intended to eliminate vitalism - such as homeostasis - before herbalism can use physiology effectively. Chaos theory, non-linear dynamics are essential components of revisioning physiology for herbalism.

Physiology + Paradigm MP3

Singh, N. P. and H. C. Lai (2005). “Synergistic cytotoxicity of artemisinin and sodium butyrate on human cancer cells.”Anticancer Res 25(6B): 4325-31.

BACKGROUND: Butyric acid is a short chain fatty acid produced by large bowel bacterial flora. It serves as an antiinflammatory agent and nutrient for normal colon cells. Butyric acid has also been shown to induce apoptosis in colon and many other cancer cells. Artemisinin is a compound extracted from the wormwood Artemisia annua L. It has been shown to selectively kill cancer cells in vitro and to be effective in treating animal and human cancer. We and others have found that the artemisinin analog, dihydroartemisinin (DHA), kills cancer cells by apoptosis. In the present study, the efficacy of a combined treatment of DHA and butyric acid at low doses in killing cancer cells was investigated. MATERIALS AND METHODS: Molt-4 cells (a human lymphoblastoid leukemia cell line) and freshly isolated human lymphocytes, cultured in complete RPMI-1640 medium, were first incubated with 12 microM of human holotransferrin at 37 degrees C in a humid atmosphere of 5% CO2 for one hour to enhance the iron concentration in the cells. Cells from each cell type were then divided into 20 flasks. These flasks were grouped into four sets of five cultures each. Zero, 5, 10 or 20 microM of DHA was added, respectively, to these sets and the cells were incubated at 37 degrees C for one hour. Zero, 1, 5, 10, or 20 mM of sodium butyrate was then added to the five cultures of each set, respectively. Thus, the treatments involved a combination of 4 doses of DHA and 5 doses of sodium butyrate. The cells were counted immediately before the addition of DHA, and at 24 and 48 hours after the addition of sodium butyrate. RESULTS: DHA alone at the 24-hour time-point and 20 microM concentration significantly reduced the number of Molt-4 cells in the culture by approximately 40% (p < 0.001, compared to non-treated control), whereas it did not significantly affect the number of normal human lymphocytes. Similarly, 1 mM sodium butyrate alone at 24 hours reduced the number of Molt-4 cells by approximately 32% (p < 0.001, compared to non-treated control), without significantly affecting normal human lymphocytes. The combination of 20 microM DHA and 1 mM sodium butyrate killed all Molt-4 cells at the 24-hour time-point and did not significantly affect lymphocytes. CONCLUSION: DHA in combination with butyric acid acts synergistically at low doses. The combination may provide a less toxic, inexpensive and effective cancer chemotherapy.

JT Comment

This is interesting! Butyrate is non toxic, and is active on its own against several cancers. Doses are likely to be high however, about 600 mg/Kg po which may be an issue. Watch this space.

New Herbal Hypotheses 2: On line prepublication

MEDLINE & The Mainstream Manufacture of Misinformation

ABSTRACT
HH2 defines and analyzes for the first time the Mainstream Manufacture of Misinformation about herbal medicine as negative propaganda about herbs which appears to be based on scientific authority of a body of scholarly literature published in medical journals indexed in MEDLINE. Definitions of science, non science, good and bad science are discussed, and the concept of “scientism” as pseudo-science is introduced. Using examples from the topic of herb-drug interactions, the MEDLINE literature is shown to be largely derivative, based upon poor quality error ridden “bad science”. The MEDLINE search engine and MESH thesaurus however confers “scientistic” or pseudoscience status to this literature. The alliance between mainstream medical establishment and pharmaceutical companies is the beneficiary and perpetrator of this process, but the MEDLINE system has hitherto not been understood as a structurally or inherently biased feature of the process. Open Access policies and the development of online informatics exemplified by Google Scholar threaten to undermine this status quo.
Download here as Herbal Hypotheses 2.pdf