If Nelsons goods are banned from being imported into the US…

August 10, 2012

…guess which US homeopathy advocate is still flogging one of their products on his website?


UK based manufacturer of homeopathic remedies Nelsons have been severely reprimanded by the US FDA for a slew of manufacturing cock-ups. [ Quackometer | FDA letter to Nelsons]

Cock-ups include:

  • “glass fragments present during the manufacture” and ” in the Clikpak Assembly”
  • “one out of every six bottles did not receive the dose of active homeopathic drug solution due to the wobbling and vibration of the bottle assembly during filling of the active ingredient. The active ingredient was instead seen dripping down the outside of the vial assembly. Your firm lacked controls to ensure that the active ingredient is delivered to every bottle.”
  • “The dosing process has not been validated appropriately. Specifically, your surrogate validation study, “Medication of un-medicated pillules with (b)(4),” visually demonstrates the variability of the amount of (b)(4) for the pillules in one vial. Your firm lacks control of the variation for the amount of the active ingredient in the pillules.”
  • “Your firm does not have an established written program to calibrate/qualify the Perkin Elmer Clarus gas chromatograph (GC) at suitable intervals.”
  • ” Your firm did not calibrate and qualify the Jasco high performance liquid chromatography (HPLC) instrumentation adequately, in that there is no periodic qualification or evaluation of the pump, oven, injector, or detector. The “Use and Calibration of HPLC” procedure does not include criteria to define adequate calibration of the instrument.”

Basically – they don’t manufacture their remedies in a controlled and consistent manner, and they cannot monitor this because it’s homeopathy, there’s nothing to monitor they don’t maintain the equipment for doing so in the correct and proper fashion.

If this was a real drug company, the implications could be disastrous. If one in six packs of antibiotics was duff, you can bet that we’d hear about that and there would be huge fines levied all round.

One wonders if users of the duff batches of remedies noticed the lack of “powerful gentle natural effective” homeopathic active ingredient, and promptly complained to Nelsons about this?

This failure to adhere to best practice has landed Nelsons on the FDA red list [Link – scroll down to United Kingdom] – “Detention Without Physical Examination of Drugs From Firms Which Have Not Met Drug GMPs” – it seems (from my reading of this notice) that Nelsons cannot export their goods to the US, and if US customers officials discover people bringing Nelsons products into the US they are to confiscate the goods. This will clearly have a negative impact on their US exports, and Nelsons are clearly rather proud of their export success [Link].

NB. Nelsons also make the Prince Charles’ Duchy Orignal line of herbal remedies [Link – Warning – Daily Mail].

So, can Nelsons products be sold in the US?

I don’t know about the legal ramification about being on the red list, but I cannot find mention of a US based manufacturing facility. Indeed, the Nelsons website states that

Our range of products meet the appropriate UK and global regulatory and licensing requirements, and are made in our Wimbledon manufacturing facility which operates to Good Manufacturing Practice (GMP) and rigorous procedures. [Link]

Clearly the FDA might have something to say about the “Good Manufacturing Practice (GMP) and rigorous procedures”.

However, as Nelsons homeopathic products are manufactured in Wimbledon, UK, it follows that any Nelsons products sold in the US must have been imported. I don’t imagine that the FDA red notice acts retrospectively, but obviously, as we are repeatedly told that “homeopathy is exceedingly popular and therefore it must work” 🙂 – one imagines that US stocks of Nelsons goods will soon run dry. I invite you to keep your eye on this page [link – warning – may cause nausea and temporary blindness ;)] to see when then this occurs.

Obviously, such a high profile and conscientious homeopath will ensure that the information on his website will remain up-to-date and entirely responsible. Moreover, given the concerns about the quality of Nelsons goods, one wonders if said homeopath will stop supplying them, to avoid the stigma of being tainted by Nelsons new-earned reputation for poor quality goods.


ASA swamped with complaints re: Homeopathy.

March 18, 2011

Quickie about a letter from the ASA to all who have complained about website with homeopathic levels of honesty.


As you may or may not be aware, the Nightingale Collaboration has co-ordinated a campaign to highlight and complain about some of the ridiculous and unsupportable claims that alternative medicine practitioners make on their websites – the current project is targeting homeopathy websites within the UK.

As someone who has complained recently about a homeopathic website or two, I recently received this bulk mail-out from the ASA:

Dear Sir/Madam

ADVERTISING CLAIMS ON HOMEOPATHY WEBSITES

Thank you for your recent complaint.

As you may know, the Advertising Standards Authority (ASA) has received over a hundred and fifty complaints about over a hundred different websites for homeopathy.  Complaints cover a range of issues from specific claims made by individual advertisers to general concerns about the sector as a whole.  Because of the volume of complaints, we are sending this letter to everyone who contacted us on these issues to let you know what action we intend to take.

The ASA has an established position on claims that can be made, and those claims that are not likely to be acceptable for homeopathy, based on the requirements set out in the CAP Code and previous ASA adjudications.  Although we have not historically received many complaints about advertising for homeopathy, the Code has general requirements for substantiation of claims in the health sector and the Committee of Advertising Practice (CAP) offers specific advice on marketing health-related products and services. Further information about the requirements of the advertising Code is available on our website www.asa.org.uk and from www.copyadvice.org.uk.

We are seeking to enforce compliance with the Code even-handedly across the sector by contacting all of the advertisers we have received complaints about as well as the bodies that represent homeopaths and homeopathy in the UK.  We will be explaining the Code’s requirements, giving advice on how to ensure advertising claims do not breach the Code, and asking advertisers to remove any claims which do not comply.  More information about what that means in practice is provided in the CAP Help Notes on Substantiation for Health, Beauty and Slimming claims and Health, Beauty and Slimming Marketing Communications that Refer to Medical Conditions.  You can find these documents on our Copy Advice website, as indicated above.  Because the ASA has only been regulating websites since 1 March many of the advertisers we contact will not be familiar with us or the work we do and will need help and assistance from us.  For that reason, we plan to monitor compliance 3 months after making our expectations of them clear. We feel that this will give advertisers, some of whom are very small and have limited resources, sufficient time to make the necessary changes.

The ASA will not be publishing individual adjudications on this occasion.  We will however publish specific, up-to-date advice to the industry and its representative bodies in due course and we will work with them to ensure that advertising for homeopathy is compliant with the Code.

Thank you for taking the trouble to contact us.  While you will not see immediate results please be assured that we are working hard in the background to resolve the issues that have been complained about.

Yours sincerely

What do I think about this?

First off  it shows that the Nightingale Collaboration (NC) has been successful in co-ordinating a fair few complaints within the 2-and-a-half weeks it has been running this campaign – whether this number of complaints matches the expectations of the NC, only they know.

It would appear that the ASA recognise that UK-based homeopaths are often making unsupportable claims about the efficacy of their sugar pills on their websites – to such an extent that they are going contact both the complained-about homeopaths and their ‘regulatory’ bodies (ARH, SoH, BHA etc) about these breaches, and make them aware of the rules that they should be adhering too. If after 3 months they have not complied with UK advertising regulations – the ASA may take further action.

Whilst individual complainers may miss out on the satisfaction of seeing adjudications against the websites they have complained about – the end result should be the same – and in fact much more far reaching. This wholesale action against all UK-homeopaths (via their ‘professional’ bodies) by the ASA should ensure that they are no longer allowed to make outrageous claims about efficacy (or claim that they were unaware of the rules).

Provided the ASA take a suitably tough line with the homeopaths, and they ensure that the rules are adhered to, I think that this can be seen as a very effective first strike by the Nightingale Collaboration.


Homeopathic guide to “conflict of interest”

March 10, 2011

Skeptics of alternative medicine are often accused of being in cahoots with the pharmaceutical industry (the “big pharma shills” argument).
Here is a ‘handy-cut-out-and-keep’ guide to COI.


I could go on…


Psorinum therapy – homeopathy for cancer?

January 31, 2011

A quick look at another paper doing the rounds


There is an update to this blog post that follows the original post


These papers [1], [2](pdf) have recently been pimped around twitter by various homeopaths, apparently as proof that a homeopathic remedy can cure cancers, including the very nasty pancreatic cancers. Paper 1 (published in a sensible-looking oncology journal) is just an abstract from a meeting, and paper 2 (published in Evidence-Based Complementary and Alternative Medicine) is the actual paper with all the juicy details – but they essentially detail the same study.

Taken on face value, the results are pretty amazing, with 5-year survival rats of around 40% for patients with stomach, gall bladder pancreatic and liver cancers (paper 2, table 3).

Compare these with current 5 year survival rates for stomach and pancreatic cancers of roughly 12% and 2% respectively.

So, if kosher – these results would be a fantastic addition to the arsenal in the war on cancer.

But…

… the studies were conducted without any controls whatsoever. The mind boggles. Why bother going to the effort of a 5 year study, and not including a control arm? Whether it be an ‘untreated’ arm, a placebo arm or a comparison against current best practices and therapies, a control arm would have increased the viability of this study no end. Even if they failed to recruit any more patients, and just split the patients into to two randomised groups with 20-odd patients in each arm, the power and impact of the study would be massively enhanced. To not control anything is just a massive fail.

This massive fail is then compounded by a failure of peer-review at eCAM. Did the reviewers not ask themselves where the controls in this study where? However, this was published in eCAM and this is clearly labelled as a prospective study – maybe I am being too harsh.

However, for those totting this paper as evidence for homeopathy curing cancer,  let’s make this absolutely clear: the only conclusions that can be drawn from this study are that the study is ultimately a waste of 5 years and is utterly meaningless in it’s current form. It should have been designed properly 5 years ago, and it should have contained some sort of control arm, and should have been properly randomised and blinded.

The authors are clearly aware of this and allude to it themselves in the final sentence of the paper:

“…randomized double-blind clinical trial, detailed molecular, pharmacokinetics,and pharmacodynamics studies should be conducted for further scientific exploration of this alternative cancer treatment to determine if it can be integrated into the mainstream oncology.”

However….

It is perhaps telling that in this final sentence in the paper, that the authors mention “detailed molecular, pharmacokinetics,and pharmacodynamics studies.” That use of the word ‘molecular’ is the only appearance of the word molecular or derivatives thereof in the entire paper, maybe unsurprising given that this is a homeopathic study.

The wonder remedy that the researchers are testing out is ‘Psnorium’ – a homeopathic remedy made from the fluid from scabies blisters (yuck) – that apparently has indications for a large number of symptoms, including, “generalities; sensitive; to pain” – well, that rules out the ~48 people on the planet that suffer from CIPA, then…

Of more note to people with an interest in molecular mechanisms (myself included), is the fact that the dilution factor used in the study is only 6x. So, 1 in 1,000,000.

Wait a minute! That’s cheating! There is an outside chance that Psnorium 6x actually has “something” in it!

Let’s assume for a minute that the results are genuine, and Psnorium 6x has had an effect on these cancers. The fluid from scabies blisters will likely contain serous fluid – but depending upon the exact contents of the blister it could contain all manner of biochemical goodies.

Given that scabies blisters are apparently intensely itchy, there may be some histamine around. The fact that the scabies mite (a foreign object) has penetrated the skin, means that some sort of immune response will have been mounted, and therefore it is inconceivable that scabies blisters would not contain some cytokines or chemokines. Was the remedy prepared from crusted or normal scabies? Because patients with crusted scabies secrete higher levels of cytokines IL-5 and IL-13, and lover levels of IFN-gamma than normal patients [3]. Other studies have shown that scabies mites, or extracts thereof alter secretion levels of a whole range of cytokines:

Active mites on the surface of the HSE induced secretion of cutaneous T cell-attracting chemokine, thymic stromal lymphopoietin, interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1ra), IL-6, IL-8, monocyte chemoattractant protein-1, granulocyte/macrophage colony-stimulating factor, and macrophage colony-stimulating factor.

So, biochemically speaking, scabies blister fluid likely contains some very interesting molecules, some of which may have an effect on cancer cells. Oral administration of Interleukins has been shown to have physiological effects in some studies, and cytokine therapy is an avenue being explored in the fight against cancer.

<Insert vaguely witty sub-heading here>

Let’s assume that the DBRCT has been done properly, and it shows a clear, statistically significant effect in cancer patients. What next? Would it be the killer blow that shows that skeptics have been wrong and homeopathy works? Sadly not – because of the likely presence of actual molecules of something. That being said, if there is an effect to be seen, it does at least give us the possibility of conducting an interesting experiment to test homeopathy:

  • Take the scabies blister fluid.
  • Give one-third of it to a homeopath, get them to make up their remedies as usual, with all the serial dilutions and succussion.
  • Give another third to a competent postgraduate student. Get them to make a 1 in 106 dilution of it, but without the homeopathic rituals like succussion.
  • Give the final third to a well-equipped, well-staffed biochemistry lab. Get them to fractionate the fluid by HPLC or FPLC, and then test the fractions for biological activity in a suitable assay, and identify the molecules present are responsible for the effect, (assuming it’s not some arm-wavy, unsubstantiated guff about the vital force or EM fields) they will presumably isolate one or more fractions that contain the molecules responsible for the therapeutic effect. These molecules could then be purified for trial in patients.

If only the homeopathic remedy recapitulates the results of the DBRCT, then homeopathy works. Elseif, science works, and someone just got lucky feeding diluted extract of scabies blister to cancer patients.

Simples.


UPDATE

A blog post at Anaximperator that I was alerted to by a pingback is well worth a look as it contains a rather interesting graph from the conference presentation that was not included in the publications –

“Psorinum+Allopathy+Homeopathy” does not look significantly different from “Psorinum+Allopathy”. “Psorinum+Homeopathy” comes a distant 3rd. The authors of the study apparently didn’t think to include an “Allopathy” or “Homeopathy” alone group. Looking at this, I would suggest that psorinum gives little, if any, benefit above and beyond the conventional treatment that patients were receiving. You will note that the only group without conventional/allopathic treatment fared significantly worse than those groups receiving it. As the anaximperator author wryly observes –  “It appears that conventional treatment is necessary for homeopathy to work.” 😉


Canadian Homeopaths plan astroturf-war

January 13, 2011

A quick note about something that popped up on my radar…


The logo of Marketplace (TV series)

Image via Wikipedia

This website (and just in case – a freezepage ) reveals that the Canadian Society of Homeopaths are planning a response to a forthcoming CBC show, Marketplace, which is running a documentary on Homeopathy. Without seeing the show (it aires on Friday, Jan 14, 2011),  it seems that the Canuck homeopaths are assuming that it puts homeopathy in a negative light (I wonder why?) and they want to get the message out so any interested parties can watch it. Fair enough.

However, their list of actions (sent out via e-mail to their members) reveals that they are also planning to bombard the Marketplace show’s blog with pro-homeopathy comments:

4. Be prepared to leave a comment on the CBC and Marketplace website immediately after the programme airs. Go to and check out the comment function right now. Sign up now to create a user’s account so that there will be no delay when you are ready to send your comments. Once the programme has aired, you can leave a comment by clicking on the title, which will take you to a summary page concluding with a link “Share your comment”. This leads to a comment box, which requires that you sign in. CBC monitors and reviews all messages so you may want to read the Submission Guidelines page before planning to send your comments.

5. Know what you are going to say so that you can post a response without delay. Choose to focus on a single point per comment, elaborate on it, and conclude with a strong, affirming statement. Often the most effective messages are short, concise, and to the point. Send as many of these as you can

They want to get their points in quickly (“leave a comment on the CBC and Marketplace website immediately after the programme airs”) but have perhaps failed to spot that unlike the Grauniad in the UK, the comments on the Marketplace blog are listed most recent first – so the early comments will soon be pushed off the bottom. They also request that their followers post as many short, concise comments as they can – essentially spamming up the comments board.

In point 7, the CSoH also warn members about falling into the same trap that UK homeopaths have fallen into regarding homeopathic for malaria vaccines.

In the second point 7, they go into full-bore, “la-la-la-I can’t hear you” mode.

la la la - I can't hear you!

How we all react to this criticism will determine how much traction this story maintains in the coming weeks and months. We urge you to be calm, be polite, be underwhelmed. Take the moral high ground. Convey that this Marketplace programme is no more than a mild irritant for homeopaths who are providing an important service in your community. It is disappointing that the CBC journalists chose to ignore the reality that is the basis of homeopathy, but that doesn’t affect what we know to be true.

The strength in homeopathy is that it works. We practitioners know it works because we see it every day in our patients and they obviously know it works because they refer their family and friends to homeopathy and they keep coming back when they get ill. Nay-sayers can say “it aint so” until they are blue in the face, but that doesn’t change the fact that homeopathy does work, even if we still don’t know how it works. Full stop. End of discussion. Let’s say what needs to be said to set the record straight and then get back to doing the important work that we do with homeopathy.

Any Canadian sceptics out there may want to keep an eye on how this astroturfing campaign proceeds 😉


Dynamised Preparations in Cell Culture?

March 15, 2010

Effects of Homeopathy in cell culture: O rly?


This post concerns this paper : “Dynamized Preparations in Cell Culture” — Sunila et al. 6 (2): 257 — Evidence-based Complementary and Alternative Medicine

I discovered this paper whilst taking a look at this website which is well worth a read, if ever feel you might want to learn about telepathic DNA (no. srsly) or absorb life threatening amounts of stupid.

Sunila et al want to look at the effect of homeopathic remedies on cells in a cell-culture setup. They also want to use homeopathic remedies rumoured to be effective in combating cancer. The hypothesis would seem to be that if the cells treated with homeopathic remedies die in cell culture then OMG! Homeopathy will cure cancer!

They use a set of homeopathic remedies, and compare mother tinctures (MTs), 30C preparations and 200C preparations.

So they take some cells, and add some homeopathic remedies to them. They then assay for stuff like cell viability (via MTT or tryptan blue exclusion method ) cell proliferation via tritiated thymidine uptake assay, and CHO cell colony formation, p53 message upregulation via RT-PCR and DNA damage via DNA laddering assay. Fine.

One of the first things that annoys the pants off me about this paper is that they seem to chop and change cells types for each different set of assays, seemingly arbitrarily. Why this is, I don’t know. If I was feeling uncharitable, I might say that this is because assay results they see only occur for certain cell types. If.

What they should have done (IMHO) is either do some experiments for all types of cells, or just use one cell type for all experiments. Chopping and changing like this makes comparison between the different assays dubious at best.

If you can’t get at the paper, or don’t want to plough through it, here are the results in bullet point form:

  • Tryptan blue exclusion method: Dalton’s lymphoma ascites &  Ehrlich ascites carcinoma cells – (figures 1 & 2 in the paper).

    • “Results on DLA cells and EAC cells were almost similar.”

      • Yes – “Almost similar” – I’ve never seen that phrase in a paper before, either.
    • Negative controls: Cells live.
    • Postive controls: There are no positive controls.
    • 200C Conium, Carcosinium,  MTs of Condurango, Hydrastis & Phytolacca and 200C preps of Thuja  & Hydratis: Some cells Die.
    • Thuja & Lycopodium mother tintcures (contain active ingredient). ~All cells die.
  • Long term viability of L929 cells is quite drastically reduced in most MTs, and to a lesser extent in some of the 30C and 200C preps (fig3).
  • They show that pretty much all their remedies, but not the controls reduce CHO cell colony formation (fig4).
  • They show that their MTs significantly reduce tritiated thymidine uptake (fig5).
  • They show that Thuja seems to induce DNA damage (fig6) and that Carcosinium seems to induce p53 expression (fig7).
  • Table 1 shows that all but one of their MTs induces apoptosis, and fewer 30C and fewer again 200C preps cause apoptosis, as determined (subjectively) by morphology.

The dye exclusion method, CHO clustering & visual assessment of apoptotic phenotype are all subjective “looking down a microscope” assays, and *may* be subject to bias. Just saying, is all.

So, we’ve got a fair old batch of results to analyse. The assays are pretty standard, and so assuming they were done competently, methodology appears fine – although there is a caveat wrt the dye exclusion assays – which measure cell viability indirectly by measuring cell membrane integrity – but probably not an issue here.

However, they do not state how many times the experiments were repeated – n=2? n=3? n=400? who knows?

There is one teensy weensy little caveat in the paper, mentioned in the methods, tucked under the table of remedies used:

“Ethanol content in the preparations may vary and no attempt was made to determine the exact content. Maximum ethanol concentration used in the experiment was 2%, which will not produce any effect on cells. Moreover results were compared with dynamized vehicle control or non-dynamized alcohol control.”

The alcohol control was only used in one assay- the p53 RT-PCR assay. All the others were controlled with “dynamized vehicle control” – which sounds like some kind of groovy new steering feature on a formula 1 car – but is, as far as I can see, just shaken phosphate-buffered saline. Which won’t contain ethanol.

But hey! Remeber, that doesn’t matter, because “Maximum ethanol concentration used in the experiment was 2%, which will not produce any effect on cells.

But they don’t provide a reference for this. This would appear to be an assumption made, and not supported, or checked, or referenced in any way.

To be fair, 2% Ethanol, doesn’t sound like much –  however, a bit of high school chemistry can show you that 2% Ethanol solution corresponds to 435mM Ethanol.

Mwt of ethanol ~ 46g
100% (pure) ethanol = 1000/46 = 21.7M
2% Ethanol = 21.7*0.02 = 0.435M Ethanol.

Which is actually a pretty high concentration. Even if the remedies only contain 1% ethanol, we’d still have 4.35mM ethanol in our cell culture, which is more than enough of a compound to have an appreciable effect in cell culture.

But we don’t know what alcohol is in the remedies – The authors didn’t check. “no attempt was made to determine the exact content” – this is really bad science. They didn’t even bother to check.

I thought it would be fun to go to the Willmar Schwabe (suppliers of the remedies) website, and see if there is any information regarding alcohol content of their remedies.

This page reveals that their mother tinctures are “The therapeutically active ingredients in many cases are extracted in alcohol-water mixture of varying percentages of alcohol depending on the solubility, stability and extractability of the potential ingredients. Such alcoholic extracts are called “Mother Tinctures”.”

So the MTs will definately contain some ethanol.
What about the 30C and 200C remedies?

Well, according to this:
“The use of genuine raw materials, back potency and expensive and purest form of alcohol, namely Extra Neutral Alcohol (ENA) make Schwabe India dilutions superior to other dilutions available in the market. Extra Neutral Alcohol guarantees that the dilutions and mother tinctures are free from impurities.”

The 30C and 200C remedies will also definately contain some ethanol.

So, to sumarise:

  1. The MTs contain planet extract in an alcohol/water mix, of unknown proportions and composition.
  2. The 30C and 200C preps contain an unknown alcohol/water mix (+ water memory of original compounds, OBVIOUSLY)

I’ve e-mailed Willmar Schwabe asking for more specific information about the composition of these remedies… as and when I get a response, I’ll update this blog post.

Given that we have established that there is most likely *some* ethanol in all these remedies, and paying particular attention to the assays caried out in Sunila et al, just what are the effects of low concentrations of Ethanol in cell culture?

1) Effects of alcohol on cell viability.

Ethanol concentrations as low as 10mM lead to increased necrosis and apoptosis (i.e. cell death), and DNA fragmentation, another assay used in Sunila et al.

Castilla, R et al, DUAL EFFECT OF ETHANOL ON CELL DEATH IN PRIMARY CULTURE OF HUMAN AND RAT HEPATOCYTES (2004) Alcohol & Alcoholism Vol. 39, No. 4, pp. 290–296, 2004 doi:10.1093/alcalc/agh065,

2) Effects of alcohol on cell clustering

“Low concentrations of ethanol (5-10 mm) inhibited cell-cell adhesion
An appreciable decrease in cell clustering is observed in low concentrations of alcohol – one of the measures of the effect of homeopathic remedies used in this paper.

Charness, ME et al. Ethanol Inhibits Neural Cell-Cell Adhesion, (1994), J. Biol. Chem, Vol. 269, No. 12, Issue of March 25, pp. 9304-9309

3) Effects of alcohol on thymidine uptake.

Suppressed levels of Thmidine uptake in the cells exposed to the MTs and remedies might be due to the fact that “alcohol levels greater than or equal to 50 mg/dL suppressed tritiated thymidine uptake of normal lymphocytes”

Glassman AB et al. Effects of ethyl alcohol on human peripheral lymphocytes. (1985) Arch Pathol Lab Med. Jun;109(6):540-2.

4) Effects of alcohol on p53 expression

Ethanol causes Oxidative stress – Sunila et al assayed for p53 expression – p53 expression known to be induced by oxidative stress.

Han, E.S. et al The in vivo gene expression signature of oxidative stress. (2008) Physiol Genomics. 12;34(1):112-26.

5) Effects of Alcohol on DNA fragmenting:

Castilla, R et al, again.

This paper shows that 10mM concentrations of Ethanol lead to increased necrosis and apoptosis, and DNA fragmentation, another assay used in Sunila et al.


Now. Given that there is published, peer-reviewed evidence that suggests that all the effects observed in Sunila et al can be explained by the presence of small amounts of ethanol, and that, the manufacturers state that all the remedies used in this Sunila et al will contain small amounts of ethanol, is it not more plausible and rational to conclude that the effects observed are caused by the small amounts of ethanol present?

Differences between different preps might be explained by different ethanol/water ratios. Differences between the effect of different MTs and MTs and 30C/200C preps can be explained by the presence in the MTs of actual, measurable amounts of chemicals that may have an effect upon cells in culture.

All this uncertainty could have been solved with a bit of Infrared spectroscopy, and better design of controls, to contain an appropriate amount ethanol.

However, such controls might well have just shown that these in vitro effects of homeopathic remedies are all down to the alcohol content. Just like Frenkel et al. (see Dr Rachie’s post and Orac’s post).

It would seem that when it comes to cell culture, homeopaths have some sort of cognitive blind spot which prevents them providing suitable controls for the solvents in which their homeopathic remedies are… remembered? One would hope that given the homeopathic preocupation with the memory of solvents, that they might remember to use the correct solvents in their controls.


IT’S TEH SILLY-CATES, STOOPID!!

February 18, 2010

A paper being touted as proof for homeopathy, by homeopaths, doesn’t really look like it does anything of the sort…


This paper, regarding silicates in succussed homeopathic solutions, is being touted as proof for a homeopathic effect, particularly by US former-Homeopath and prolific Homeopathy advocate, Dana Ullman.

http://twitter.com/HomeopathicDana/status/9271036920 (Screengrab in case of deletion)

Enzyme stabilization by glass-derived silicates may explain #homeopathy mechanism. #ten23 http://tinyurl.com/ylkggbg

Obviously, it does nothing of the sort, and in fact, it just provides another potential source of false-positive in trials involving homeopathic remedies.

The paper suggests that the act of succussion (striking a homeopathic remedy against a leather-backed object) during production knocks silicates from the glass into the solution. The paper continues “silicates and other solutes are present at micromolar levels in all glass-exposed solutions, whether pharmaceutical or homeopathic in nature.”

In a nutshell, the paper does the following:

  • They conduct a series of tests with acetylcholine esterase to assay for enzyme stabilisation (enzyme activity after incubation for 24hours in various silicate containing solutions, succussed and un-succussed controls). Without delving into too much detail, the assays are fairly bog-standard endpoint assays conducted with a colourimetic substrate (a substrate analogue that changes colour upon reaction) and assayed for colour change in 96-well format in a standard issue plate reader. All standard biochemistry stuff. I’ve done a couple of plasmin activity assays this week myself using a very similar technique. Fine. They show that succussed solutions have an enhanced stabilsation effect over un-succussed solutions.
  • They also conduct some ICP-OES experiments and show that succussed solutions have ~3mg/ml silicates & boron and sodium present – more than un-succussed solutions.
  • They do some molybdate assays to show that homeopathic remedies (they looked at 30C Arsenicum, 200C Arsenicum and 30C Glutamate) contain a similar level of silicates present.
  • They then show that a 30C water solution has a similar effect on acetylcholine esterase as a 100uM solution of NaOH/Silicates.

The paper concludes “Nonetheless, future in vitro homeopathic experiments will need to take into account the fact that significant levels of dissolved solids exist in glass-exposed solutions, and that these can have functional effects on proteins dissolved therein.

There isn’t an awful lot wrong with the paper, to be honest. It’s the homeopaths interpretation I have issue with.

This is the train of thought, as far as I can tell:

  1. Succussed solutions contain silicates at a concentration on the order of ~100uM. YES.
  2. These silicates have a demonstrable biological effect on certain enzymes in in vitro assays. YES
  3. Therefore silicates in homeopathic solutions are the seat of the efficacy of homeopathic remedies. EH?

Lets ignore the myriad caveats about scaling up from in vitro to in vivo, for just a minute. Oh yes, and the fact that the silicates found in these remedies are unremarkable, and will be found in any solution that has been exposed to glass. Oh, and that the levels of silicates found in homeopathic remedies are WAY below the level of silicates that you might find in a normal diet. As the authors note.

The fact that they are present in all three remedies tested (and the authors suggest, all homeopathic remedies produced in this way), means that silicates cannot POSSIBLY be the source of any sort of efficacy or healing effect

Given that homeopathic remedies, irrespective of the contents of the original tincture, will contain these silicates (and indeed, any solution in a glass container that has been roughly handled), how can they be responsible for the supposed healing effect of say, 30C arnica for bruising, AND for say, 30C belladonna, in whatever the heck 30C belladonna is supposed to cure?

In fact what this paper does do is give another potential explanation for the very minor effects sometimes observed in certain in vitro trials which aren’t properly controlled. Which is clearly what the authors wrote the paper and conducted the experiments to address. They also mention that conventional pharmaceuticals stored in glass would also likely have similar levels of silicates in them.

Really, the authors make it pretty damn clear what it is that they have researched, and it certainly isn’t a potential mechanism for homeopathy, rather the dissolution of silicates from glass vessels into solutions which then has an effect on in vitro assays for a specific enzyme.

I.e – if you are lucky enough to see any in vitro effect from a homeopathic remedy, it isn’t the arsenic that was once in it, IT’S TEH SILLY-CATES, STOOPID!!

Actually, seeing as we’re on silicates, the Biomineral research section of the MRC centre in human nutrition research hypothesise that silicate absorbtion in the gut “result(s) in detrimental responses in susceptible individuals such as those with inflammatory bowel diseases.”

So we should perhaps conclude that homeopathic remedies should be avoided by people with inflammatory bowel disesases, such as Crohn’s disease and Ulcerative Colitis.


Mis-quoting. Quote mining. Quotology. Quotography. LYING.

February 11, 2010

A little piece about mis-quotage, and how it irks me so.


In the space of about 12 hours this week, I read two articles concerning the gross perversion of peer-reviewed scientific literature, and people selectively quoting from said peer-reviewed publications to push forward their own agendas.

The first was Martin Robbins excellent demolition of the BHA’s evidence to parliament. This comes in two parts – the Guardian Article, and his response to the BHA response.

I have touched upon homeopaths doing this before, so it should come as no surprise really.

A particularly insidious example (taken from Martin’s blog at layscience.net) was:

BHA

Cucherat 2000: “There is some evidence that homeopathic treatments are more effective than placebo.”

The full, unabridged quote

There is some evidence that homeopathic treatments are more effective than placebo; however, the strength of this evidence is low because of the low methodological quality of the trials. Studies of high methodological quality were more likely to be negative than the lower quality studies.

Lets us be crystal clear about what is going on here – this is not a mistake. This is not a simple error or omission. Nor is it stupidity or incompetence.

This is lying. Deliberate misdirection. Fabrication. Falsification. Bearing false witness. Mendacity. Fraud. You get the idea.

In the case of the BHA, they misrepresented evidence in front of the UK parliament science and technology committee.

The report is due out on the 22/02/10. I’ll wait and see how far their mendacity gets them.

The second instance of quote-mining lying was discussed in the Guardian piece on how climate change skeptics has mis-quoted the e-mails (so not peer-reviewed) leaked in “climate gate”. Now I’m not a climate scientist, (If you want more info, go to Andy Russell’s excellent blog. He is a climate scientist) but it strikes me that this is probably more important, in that it potentially effects the whole world, and not just the UK. “Climategate” was touted in the international press, and by climate change “skeptics” including Sarah Palin., as example of how global warming is not real, and it is just an artefact created by climatologists… for what reason I have yet to fathom.

(Note: As a general rule –  If Sarah Palin agrees with you then there is a very good chance you are wrong.)

The most prominent example of quote-mining in this case was saying that “tricks” were used to alter/obscure data when they were in fact referring to a visual trick to display data.

The trouble facing people at the wrong end of these mis-quotes, is that the initial mis-quote is often seized upon by the press, and then hurtles around the world faster than you can say “Intergovernmental Panel on Climate Change”. The following “erm, actually, I think you’ll find” article rarely gets any coverage, and thus, the general public only see the lies. In such cases the ball lies firmly in the court of the media – “erm, actually, I think you’ll find” articles are not big and sexy – but they are an incredibly important part of maintaining journalistic integrity, and ensuring that the general public is kept well informed. After all, we cannot expect a democracy to make informed choices when the voting public do not have the necessary information.

The point I am trying to get around to making (probably quite badly,) is that the nature of peer-review keeps scientists honest. This is important, as it tends to have the effect of removing personal bias, hyperbole and egos from the science discussed. It may not be perfect – but it is the best system we have for ensuring that good science is published, and bad science is weeded out.

Perversion of peer-reviewed articles and of scientific discourse in general is the domain of the quack and the charlatan – the fact that the BHA and climate change skeptics have resorted to such underhand tactics speaks volumes about their integrity.


Homeopathy and Anaesthesia.

February 6, 2010

Addressing the oft-repeated mantra – “you don’t know how anaesthetic works”


When considering homeopathy, an obvious bone of contention is the lack of a plausible molecular mechanism .

When proffering this as a reason why homeopathy is not feasible, a homeopath will typically counter with “well what about anaesthesia – we don’t know how that works either.”

So lets explore this a little further…

“General anaesthesia is administered each day to thousands of patients worldwide. Although more than 160 years have passed since the first successful public demonstration of anaesthesia, a detailed understanding of the anaesthetic mechanism of action of these drugs is still lacking.” So states the opening gambit of an excellent and fairly recent review of the potential receptors for general anaesthetics.

Kopp Lugli, A., Yost, C.S. and Kindler, C.H. (2009) “Anaesthetic mechanisms: update on the challenge of unravelling the mystery of anaesthesia”. European Journal of Anaesthesiology, 26(10), p 807–820

A general anaesthetic has to do three things: cause immobility, amnesia and unconsciousness. Many potential molecular targets are being researched – these are summarised in the table below.

Taken directly from Kopp Lugli, A., Yost, C.S. and Kindler, C.H. (2009) “Anaesthetic mechanisms: update on the challenge of unravelling the mystery of anaesthesia”. European Journal of Anaesthesiology, 26(10), p 807–820. Fair use claimed.

We don’t know for sure what all the molecular targets are, but Franks, N.P. (2006) “Molecular targets underlying general anaesthesia” Br J Pharmacol. 147(S1): S72–S81, is a decent review of what is known about the molecular mechanism of two types of Anaesthetic, propofol and etomidate, and their interaction with the GABA-A receptor. The GABA-A receptor is a ligand-gated ion-channel, a complex of proteins that allows ions (in this case Chloride ions) to cross an otherwise impermeable membrane. GABA-A receptors are found in most areas of the brain. Propofol and etomidate are positive allosteric modulators of the ion channel – they bind at a site on the ion-channel distinct from the pore through which the ions pass and make the ion-channel more easily openable, and Cl- ions can flow freely accross the membrane. This will lead to hyperpolarization of the neurons, which in turn, inhibits neurotransmission, which eventually leads to the anaesthetic effect.

Science doesn’t know the precise ordering of molecular events that leads to sucesful anaestheisia – but it is working on it – and it is making progress. But for all anaesthetics we have “leads” – potential, rational, explainable targets for their mode of action.

So we actually know a lot more about the mechanism of action of anaesthetics, than we do about homeopathy.

Now lets look at the formulation of a typical general anaesthetic.

Propofol is distributed as Diprivan – a 1% solution in combination with various inert stabilisers and anti-microbial agents.

The dosing guidlines for Diprivan states: “adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, DIPRIVAN Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia. ”

Lets assume we have a 100kg adult, and we are going to dose them at 2.5 mg/kg.

So that’s a total of 2.5mg x 100 = 250mgs of Diprivan.

The molecular weight of propofol is 178.271 g/mol.
This is 0.25g / 178.271 = 0.00140235 moles of Diprivan.

Multiply this by Avagadro’s Constant and you discover that this 250mgs has got 8.44×10^20 molecules of pharmacologically active ingredient.
844,000,000,000,000,000,000 molecules.

Contrast this with a Homeopathic anaesthetic, which would have zero molecules of pharmacologically active ingredient.

Interestingly enough, given all the things homeopathy claims to cure (cancer, AIDS, Homosexuality, etc) – a cursory piece of googlage actually reveals that one of the few things homeopathy doesn’t claim to do is general anaesthetic – fear of pain is a great leveller, I guess.

(If you can find a reference to a Homeopathic Anaesthetic – please leave a comment below!)

However, homeopaths naturally claim that homeopathy can help with after effects of anaesthesia and surgery – after effects which coincidentally, will resolve naturally more often than not.

This reference sheet entitled “Homeopathic support during surgery” is particularly shocking.

The first thing to note is that it states: “Use 30c potency for these acute treatments.”
As previously established – 30c potency contains zero pharmacologically active molecules.

Of all the treatments outlined by this sheet – the most dangerous and irresponsible are those that detail treatment for symptoms of surgical site infection (SSI).

“Hepar Sulph wounds that have become weeping and pustulent”
“Pryogen indicated when there is necrosis, gangrene or dead flesh, in the wound”

That is exceptionally irresponsible – Between 5% and 10% of people who undergo an operation suffer from an SSI. Dangerous pathogenic bacteria such as MRSA and Clostridium difficile can thrive in the wounds left after surgery, and if left unchecked, infection can be fatal. The correct treatment for an SSI is antibiotics.

If anyone were to rely on homeopathy rather than conventional antibiotics, they would be putting their lives in jeopardy.


Clutching at homeopathic straws?

January 29, 2010

“Oooh! A new and exciting area of science – does it have big, important-sounding words? EXCELLENT – could it in anyway concievably be applied to homeopathy? F**k it! That’ll do!”


One of the many claims that Homeopathy makes is that of the “Similia Principle” or “like cures like”. It is this principle by which a homepath selects a remedy: Patient presents with symptom X. Compound Y causes symptom X. Give patient an ultramolecular dilution of compound Y to treat symptom X.

In the recent edition of Homeopathy “Special Issue: Biological models of homeopathy Part 2” a paper entitled “The similia principle: Results obtained in a cellular model system” concludes that

“results support the similia principle at the cellular level and add to understanding of how low dose stress conditions influence the regulatory processes underlying self-recovery”

They then document some experiments in which cells that are exposed to a high dose of “stress” (heat shock, or toxic compounds such as Arsenic or Cadmium) cope better with and react more intensly to a subsequent low dose of stress. Why this is surprising, I do not know. Adaptive responses and/or preconditioning of cells (both prokaryotic and eukaryotic) is well researched. A pubmed search for adaptive response generates over 17000 hits, for preconditioning over 8000. (correct as of Jan 29th 2010).

On a cellular/molecular level, this can be explained by more rapid production/activation of certain stress response proteins, such as heat shock proteins and protein folding chaperones – proteins which attempt to either prevent or reverse that damage caused by whatever stress factor is currently blighting the cell’s ability to proliferate and survive. The more rapid response to the second exposure to stress might be as a result of residual levels of certain transcription factors or activators within the cells. This is not explored in the paper. Another possibility is that the cells that survived the initial high dose of stress are intrinsically better able to adapt to the stress, either as a result of mutation or cellular niche or various other arm-wavey possibilities. The first assult with the stress causing compound has naturally selected for those cells with a better chance of survival – this is the basis of something called “Evolution.” Google it. I’m told It’s quite popular.

At the level of an organism, this is basically describes an immune system. An organism is confronted with a “stress”. The organism develops a response (e.g antibodies) to the stress. Next time the stress is encountered, response molecules are quickly produced in massive quantities to prevent damage from stress. Surely everyone saw this graph in GCSE/’A’-level biology?

Source

It’s the basis by which all vaccines work, and how multicellular life responds to any sort of antigen. Very basic stuff. Hence It was taught at GCSE level (at least when I sat GCSE Biology in the early 90s).

This paper, however, does things differently – high dose first, then low dose – and seems to find some extra significance in this. Why? The relative sizes of the doses are immaterial, as long as cells/organism survive, it is now primed to respond to a second insult. IMHO, a more interesting study ( at least on a cellular/molecular level) would be how long does this “priming of the system” last? Does that time correlate in any way with known half lives for mRNA, transcription factors, phosphorylation of various proteins? Is this persistence of this effect related to the size of the initial insult? This is not commented on.

Figure 1 is a nice little diagram of their experimental design.

Fig 1 from here – used without permission, but fair use claimed.

There are two incredibly obvious ommissions in this experimental design…

Low dose, high dose, evaluate.

Low dose, no treatment, evalute.

I imagine that this has been done before – and if I was feeling mean I might suggest that the results maybe very similar to the “high dose/low dose” regimen, and have been ommited –  but irrespsective of this –  one needs to replicate this in your experimental design as a control. Ooops.

But that’s really nitpicking – important nitpicking, IMHO, but nitpicking nevertheless.

They then go on to use these observations to support the basic tenets of homeopathy.

<Screeeeeeech> <double take> Woah there! Did I miss something?
  1. All these experiments are done with actual measurable amounts of compounds present (10uM, 0.3uM – handy, easy to understand concentrations like that). Unlike homeopathic remedies.
  2. When treating someone with a homeopathic remedy, the patient will persumably be taking the *cough* low dose1 *cough* at the same time as he/she is suffering with the effects of the high dose (note – Homeopathy treats symptoms, not causes – so it is easy to see how they might overlook this). So even if the concept of hormesis is real and valid in this context (and there is some controversy about that) what is the biological mechanism by which this occurs? After all a very big number plus a very small number is still a very big number – how does the body determine which compound is for what purpose?
This support of homeopathy is realised though some arm-waving about “postconditioning hormesis” – sadly not ultra-diluted molecules administered after the onset of the symptom travelling back in time to pre-condtion the body before the onset of the symptom and confer partial-immunity, thus helping the patient get better back in the future.
We have a reference to postconditioning in the context of myocardial infarctions – and a reference to a paper which seems to do a decent job of describing postconditioning and then going on to have a stab at getting some clues about the mechanism by which the postconditioning limited the damage caused by the previous myocardial infarction. So postconditioning – fine – plenty of evidence for that in certain contexts.
And then there is reference to hormesis – where giving a small dose of something gives opposite effect of large dose – ok – fine – some examples of that in the literature, (e.g. in context of aging,) but with a caveat that whilst it is an interesting hypothesis, predictions made on the basis of hormesis are not suitably accurate for directing health care choices, policy etc.
Stitch the two together and “POSTCONDITIONING HORMESIS” is born. Orginally toted in this paper – postconditioning hormesis is a strange and intriguing effect – but you can imagine how it might work – low levels of non-damaging stress shortly after major damaging-stress prolong the synthesis/activation of response factors that aid recovery and limit damage – i.e. it is explainable by current scientific thinking – as long as one believes in such vagaries as “avagardos constant” and what have you.
Given that it involves a beneficial small dose been given after stress caused by a toxic high dose, it is perhaps not surprising that Homeopathy has lept upon postconditioning hormesis as a potential mechanism through which it might work. A google search of “postconditioning hormesis” reveals that 6 of the 10 hits on the first page also mention homeopathy. Peter Fisher, the UKs homeopath-in-chief, even mentions it in his lectures now.
However in jumping on the postconditioning hormesis band wagon, Homepathy has seemingly bypassed other, more thorny issues like the mechanism of succussion, lack of evidence for the “memory of water” and the subsequent “memory of sugar” and the molecular mechanism by which this memory is realised in the context of binding to receptor molecules, not-to-mention the ever present “lack of efficacy beyond placebo effect” issue that it suffers from.
For the homeopaths to jump on this phenomenon before it is fully understood and claim it as potential proof for the Similia principle looks awfully like another attempt to dupe the public with important sounding pseudo-scientific waffle…
A bit like this:
It’s clutching at straws.
—-
1 By “low dose”, I of course mean “no dose” – a ultra-dilute potentized solution containing zero active molecues – other than the water and the impurities within. With the memory of the original high dose molecule… transfered to a sugar pill. Got that?