Chemical connections: dexamethasone, hydroxychloroquine and rheumatoid arthritis

The chemical structure of dexamethasone (image from Wikimedia Commons)

It’s been widely reported today that a “cheap and widely-available” steroid treatment has been shown to be effective in patients suffering the most severe COVID-19 symptoms, significantly reducing the risk of death for both patients on ventilators and those on oxygen treatment.

Most of the reports have understandably focused on the medical aspects, but this is a chemistry blog (mostly) so *cracks chemistry knuckles* what is dexamethasone, exactly?

Its story starts a little over 60 years ago when, in 1958, a paper was published on “clinical observations with 16a-methyl corticosteroid compounds”. Bear with me, I shall explain. Firstly, corticosteroids are hormones which are naturally produced in our bodies. They do all sorts of nifty, useful things like regulate our immune response, reduce inflammation and help us to get energy from carbohydrates. Two of the most familiar names are probably cortisol and cortisone—both of which are released in response to stress.

The discovery of corticosteroids was an important one. So important, in fact, that a few years earlier, in 1950, Tadeusz ReichsteinEdward Calvin Kendall and Philip Showalter Hench had been awarded a Nobel Prize in Physiology and Medicine for “discoveries relating to the hormones of the adrenal cortex”.

The adrenal glands are two small glands found above the kidneys. The outermost part of these glands is called the adrenal cortex (“cortex” from the Latin for (tree) bark and meaning, literally, an outer layer). In the mid-1930s Kendall and Reichstein managed to isolate several hormones produced by these glands. They then made preparations which, with input from Hench, were used in the 1940s to treat a number of conditions, including rheumatoid arthritis.

This was hugely significant at the time, because until this point the treatments for this painful, debilitating condition were pretty limited. Aspirin was known, of course, but wasn’t particularly effective and long-term use had potentially dangerous side effects. Injectable gold compounds (literally chemical compounds containing Au atoms/ions) had also been tried, but those treatments were slow to work, if they worked at all, and were expensive. The anti-malarial drug, hydroxychloroquine (which has also been in the news quite a lot), had been tried as a “remittive agent”—meaning it could occasionally produce remission—but it wasn’t guaranteed.

Rheumatoid arthritis causes warm, swollen, and painful joints (image from Wikimedia Commons)

Corticosteroids were a game-changer. When Hench and Kendall treated patients with what they called, at the time, “compound E” (cortisone) there was a rapid reduction in joint inflammation. It still caused side effects, and it didn’t prevent joint damage, but it did consistently provide relief from painful symptoms.

Fast-forward to the 1958 paper I mentioned earlier, and scientists had discovered that a little bit of fiddling with the molecular structure of steroid molecules caused them to have different effects in the body. The particular chemical path we’re following here started with prednisolone, which had turned out to be a useful treatment for a number of inflammatory conditions. However, placing a methyl group (—CH3) on the 16th carbon—which is, if you have a look at the diagram below, the one on the pentagon-shaped ring, roughly in the middle—changed things.

The steroid “nucleus”: each number represents a carbon atom (image from Wikimedia Commons)

In 1957, four different molecules with methyl groups on that 16th carbon were made available for clinical trial. One of them was 16a-methyl 9a-fluoroprednisolone, more handily known as dexamethasone.

(Quick aside to explain that on the diagram of dexamethasone at the start of this post, the methyl group on the 16th carbon is represented by a dashed wedge-shape. It’s a 2D diagram of a 3D molecule, and the dashed wedge tells us that the methyl group is pointing away from us, through the paper, or rather, screen. This matters because molecules like this have mirror image forms which usually have very different effects in the body—so it’s important to get the right one.)

Dexamethasone is on the WHO Model List of Essential Medicines

It turned out that dexamethasone had a much stronger anti-inflammatory action than plain prednisolone, and it was also more effective the other molecules being tested. It caused a bigger reduction in symptoms, at lower doses. A win all round. It did still have side effects—weight gain, skin problems and digestive issues—but these were no worse than other steroids, and better than some. In fact, salt and water retention were less with dexamethasone, which meant less bloating. It also seemed to have less of an effect on carbohydrate metabolism, making it potentially safer for patients with diabetes.

Skipping forward to 2020, and dexamethasone is routinely used to treat rheumatoid arthritis, as well as skin diseases, asthma, COPD and various other conditions. It is on the WHO Model List of Essential Medicines—a list of drugs thought to be the most important for taking care of the health needs of the population, based on their effectiveness, safety and relative cost.

In the wake of more and more evidence that COVID-19 disease was leading to autoimmune and autoinflammatory diseases, scientists have been looking at anti-inflammatory drugs to see if any of them might help. The Recovery Trial at the University of Oxford was set up to investigate a few different drugs, including hydroxychloroquine (there it is again) and dexamethasone.

It’s not a miracle cure but, in the most severe cases, dexamethasone—a cheap, 60+ year old drug—might just make all the difference.

And that brings us back to today’s news: in the trial, 2104 patients were given dexamethasone once per day for ten days and compared to 4321 patients who were given standard care. The study, led by Professor Peter Horby and Professor Martin Landray, showed that dexamethasone reduced the risk of dying by one-third in ventilated patients and by one fifth in other patients receiving only oxygen.

It’s not a miracle cure by any means: it doesn’t help patients who don’t (yet) need respiratory support, and it doesn’t work for everyone, but, if you find yourself on a ventilator, there’s a chance this 60+ year-old molecule that was first developed to cure rheumatoid arthritis might, just, save your life. And that’s pretty good news.

EDIT 17th June 2020: Chemistry World published an article pointing out that “the trial results have yet to be released leading some to urge caution when interpreting them” and quoting Ayfer Ali, a specialist in drug repurposing, as saying “we have to wait for the full results to be peer reviewed and remember that it is not a cure for all, just one more tool.


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Hazardous homeopathy: ‘ingredients’ that ought to make you think twice

Would you take a medicine made with arsenic? Or deadly nightshade? Lead? Poison ivy?

You’d ask some serious questions first, at least, wouldn’t you? Is it definitely safe? Or, more accurately, are the odds better than even that it will make me better without causing horrible side-effects? Or, you know, killing me?

There ARE medicines that are legitimately made from highly toxic compounds. For example, the poison beloved of crime writers such as Agatha Christie, arsenic trioxide, is used to treat acute promyelocytic leukemia in patients who haven’t responded to other treatments. Unsurprisingly, it’s not without risks. Side-effects are unpleasant and common, affecting about a third of patients who take it. On the other hand, acute promyelocytic leukemia is fatal if untreated. A good doctor would talk this through with a patient, explain both sides, and leave the final choice in his or her properly-informed hands. As always in medicine, it’s a question of balancing risks and benefits.

Would you trust something with no proven benefit and a lot of potential risk? There are, it turns out, a swathe of entirely unregulated mixtures currently being sold in shops and online which clearly feature the substances I listed at the beginning. And more. Because they are all, supposedly, the starting materials in certain homeopathic remedies.

Homeopaths like to use unfamiliar, usually Latin-based, names which somewhat disguise the true nature of their ingredients. Here’s a short, but by no means comprehensive, list. (You might find remedies labelled differently but these are, as far as I can tell, the most common names given to these substances.)

If you haven’t heard of some of these, I do urge you to follow the links above, which will largely take you pages detailing their toxicology. Spoiler: the words “poison”, “deadly” and “fatal” feature heavily. These are nasty substances.

There are some big ironies here, and I’m not referring to the metal. For example, a common cry of anti-vaccinationists is that vaccines contain animal tissues – anything and everything from monkey DNA to dog livers. But many also seem to be keen to recommend homeopaths and courses of homeoprophylaxis – so-called “homeopathic vaccines” – which use bodily fluids such as pus and blood as starting materials.

Now, at this point I’m sure some of you are thinking, hang on a minute: aren’t you always telling us that “the dose makes the poison“? And aren’t homeopathic remedies diluted so much that none of the original substance remains, so they’re just placebos?

Yes, I am, and yes, they are.

Does anyone test homeopathic remedies to make sure there’s nothing in them….?

In THEORY. But here’s the problem: who’s testing these mixtures to make sure that the dilutions are done properly? And how exactly are they doing that (if they are)?

One technique that chemists use to identify tiny quantities of substance is gas chromatography (GC). This is essentially a high-tech version of that experiment you did at school, where you put some dots of different coloured ink on a piece of filter paper and watched them spread up the paper when you put it in some water.

GC analysis is brilliant at identifying tiny quantities of stuff. 10 parts per million is no problem for most detectors, and the most sensitive equipment can detect substances in the parts per billion range. Homeopathy dilutions are many orders of magnitude higher than this (30c, for example, means a dilution factor of 1060), but this doesn’t matter – once you get past 12c (a factor of 1024) you pass the Avogadro limit.

This is because Avogadro’s number, which describes the number of molecules in what chemists call a “mole” of a substance, is 6×1023. For example, if you had 18 ml of water in a glass, you’d have 6×1023 molecules of H2O. So you can see, if you’ve diluted a small sample by a factor of 1024 – more than the total number of molecules of water you had in the first place – the chances are very good that all you have is water. There will be none of the original substance left. (This, by the way, is of no concern to most homeopaths, who believe that larger dilutions magically produce a stronger healing effect.)

What if the sample ISN’T pure water after it’s been diluted?

If you carried out GC analysis of such a sample, you should find just pure water. Indeed, if you DIDN’T find pure water, it should be cause for concern. Potassium cyanide, for example, is toxic at very low levels. The lethal dose is is only 0.2-0.3 grams, and you’d suffer unpleasant symptoms long before you were exposed to that much.

So what if the dilutions somehow go wrong? What if some sample gets stuck in the bottle? Or on the pipette? Or a few dilution steps get skipped for some reason?

Are these largely unregulated companies rigorously quality-checking their remedies?

Well, maybe. It’s possible some producers are testing their raw materials for purity (ah yes, another question: they CLAIM they’re starting with, say, arsenic, but can we be certain?), and perhaps testing the “stability” of their products after certain periods of time (i.e. checking for bacterial growth), but are they running tests on the final product and checking that, well, there’s nothing in it?

And actually, isn’t this a bit of a conflict? If the water somehow “remembers” the chemical that was added and acquires some sort of “vibrational energy”, shouldn’t that show up somehow in GC analysis or other tests? If your tests prove it’s pure water, indistinguishable from any other sample of pure water, then… (at this point homeopaths will fall back on arguments such as “you can’t test homeopathy” and “it doesn’t work like that”. The name for this is special pleading.)

A warning was issued in the U.S. after several children became ill.

Am I scaremongering? Not really. There’s at least one published case study describing patients who suffered from arsenic poisoning after using homeopathic preparations. In January this year the U.S. Food and Drug Administration issued a warning about elevated levels of belladonna (aka deadly nightshade) in some homeopathic teething products. Yes, teething products. For babies. This warning was issued following several reports of children becoming ill after using the products. The FDA said that its “laboratory analysis found inconsistent amounts of belladonna, a toxic substance, in certain homeopathic teething tablets, sometimes far exceeding the amount claimed on the label.”

Now, admittedly, I’m based in the U.K. and these particular teething remedies were never readily available here. But let’s just type “homeopathy” into the Boots.com (the British high-street pharmacy) website and see what pops up… ah yes. Aconite Pillules, 30c, £6.25 for 84.

What happens if you search for “homeopathy” on the Boots.com website?

Have you been paying attention lovely readers? Aconite is…. yes! Monkshood! One of the most poisonous plants in the garden. Large doses cause instant death. Smaller doses cause nausea and diarrhea, followed by a burning and tingling sensation in the mouth and abdomen, possibly muscle weakness, low blood pressure and irregular heartbeat.

I must stress at this point that there is no suggestion, absolutely none whatsoever, that any of the products for sale at Boots.com has ever caused such symptoms. I’m sure the manufacturers check their preparations extremely carefully to ensure that there’s absolutely NO aconite left and that they really are just very small, very expensive, sugar pills.

Well, fairly sure.

In summary, we seem to be in a situation where people who proclaim that rigorously-tested and quality-controlled pharmaceuticals are “toxic” also seem to be happy to use unregulated homeopathic remedies made with ACTUALLY toxic starting materials.

I wonder if the new “documentary” about homeopathy, Just One Drop, which is being screened in London on the 6th of April will clarify this awkward little issue? Somehow, I doubt it. Having watched the trailer, I think it’s quite clear which way this particular piece of film is going to lean.

One last thing. Some homeopathic mixtures include large quantities of alcohol. For example, the Bach Original Flower Remedies are diluted with brandy and contain approximately 27% alcohol (in the interests of fairness, they do also make alcohol-free versions of some of their products and, as I’ve recently learned, they may not be technically homeopathic). Alcohol is a proven carcinogen. Yes, I know, lots of adults drink moderate quantities of alcohol regularly and are perfectly healthy, and the dose from a flower remedy is minuscule, but still, toxins and hypocrisy and all that.

There are cheaper ways to buy brandy than Bach Flower Remedies.

Amusingly, the alcohol in these remedies is described an “inactive” ingredient. It’s more likely to be the only ACTIVE ingredient. And since Flower Remedies retail for about £7 for 20 ml (a mighty £350 a litre, and they’re not even pure brandy) may I suggest that if you’re looking for that particular “medicine” you might more wisely spend your money on a decent bottle of Rémy Martin?


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Vaccines are one of humankind’s best achievements, and we should all be shouting about it

science-fiction-1819026_960_720Imagine aliens finally get around to visiting our planet…

“About two hundred years ago,” explains the alien scientific advisor – let’s call him Spuck – “humans developed a way to prevent disease which they call vaccination. It’s really quite fascinating. They use a needle to place a tiny quantity of a fluid into the muscle under the skin of their arm or leg. The substances are then absorbed into their bodies and cause their highly-evolved immune systems to generate an immune response without, and this is really quite ingenious, Captain, their having to contact the actual diseases or suffer the symptoms. This simple procedure has saved millions of lives worldwide, and saved many millions more from having to suffer less fatal, but none the less still deeply unpleasant, consequences of serious illnesses.”

“Sounds great, Spuck,” says the Captain – let’s call him Birk – “is there a downside?”

“Not really, Captain. Side effects are rare and extremely minor compared to the seriousness of the illnesses themselves.”

“Fantastic. Why are you telling me all this? I’ve got some green-skinned action I’d like to get back to, if you know what I mean.”

“Well, it’s interesting that you should mention unusual skin tones, Captain. A leader has recently come to power who, amongst other things, has expressed concerns about vaccination.

“Valid concerns?”

“The scientific evidence suggests not, sir.”

“Sounds like an idiot, Spuck.”

“I couldn’t possibly comment, sir.”

“Huh. Sounds like he could definitely be detrimental to the future of their race, and besides, I’m bored. Let’s go and shoot some stuff in direct contravention of the Cardinal Directive. Set blazers to ki- I mean, stun. Beam me down, Dottie!”

***

Vaccination. It’s a hot topic at the moment, and one which is so important that I think anyone who has anything to do with science communication ought to be talking about it. I’m not a medical doctor, or an immunologist, or even a biochemist (for more qualified input on the subject, I refer you here, here and here), but I AM capable of recognising scientific consensus and of separating good-quality evidence-based information from conspiracy theory dross.

Vaccination is awesome.

Awesome is a word that is somewhat overused. But I mean it literally. As in, inspires awe. We should stop, for a moment, and just look at how bloody amazing vaccination is. Thanks to these simple, near-painless, injections – most of which we receive as young children and therefore don’t even remember – we are largely protected from the horrors of….

  • Poliosymptoms and complications include fever, vomiting, headache, back pain, joint pain and stiffness, permanent muscle weakness, permanent paralysis and death.
  • Mumpssymptoms and complications include fever, headache, meningitis, painful testicular swelling in males and ovarian inflammation in females, both of which can  result in permanent infertility, pancreatic inflammation and, occasionally, hearing loss. Death from mumps is rare, but does occur in about 1 in 10,000 cases.
  • Tuberculosis – symptoms and complications include fever, loss of appetite, severe fatigue, chest pain, coughing up of blood, scarring of the lungs, internal bleeding and death (death is considerably more likely if the patient does not have access to medical care).
  • Measlessymptoms and complications include fever, painful skin rash, diarrhoea, vomiting, ear infection which can result in deafness, eye infection which can result in blindness, laryngitis, pneumonia, bronchitis, liver infection, encephalitis, and increased likelihood of re-contracting diseases previously survived (measles essentially “wipes” your immune system). Oh yes, and death. As many as 1% of measles patients will die from the disease.

… and umpteen other, horrible diseases, the majority of which most people reading this will have never experienced. Because of vaccination.

Measles rash

A child with a measles rash. The disease can cause serious complications, including immune suppression.

The risks of vaccination are tiny. The most common complications are redness and swelling around the injection site and/or slight temperature which is easily treated with an antipyretic such as paracetamol or ibuprofen. Very occasionally people suffer a serious allergic reaction, but this inevitably happens quickly after the injection is given. Since vaccinations are usually administered in a medical setting, any allergic reaction that does occur can be quickly managed. There have been a few other genuine cases of serious, adverse reactions to vaccines, but problems are still very rare (the swine flu-narcolepsy link, for example, affected 1 in 55,000) and specific to particular vaccines, and the vaccine in question has been quickly investigated.

Like Birk, if you’ve had nothing to do with the anti-vaccination community, you may be thinking this all sounds good. Benefits massive, risks tiny. Fab. Let’s go.

However, the anti-vaccination crowd – a real, and not entirely new, thing – will tell you that this is all lies. They will tell you this loudly, and at length, and repeatedly. They believe that vaccinations cause every health problem from acne to zygomycosis, but particularly the neurodevelopmental condition known as autism.

Vaccines do not cause autism. At all. As Spuck said, the scientific evidence is clear. It’s absolutely ice-from-a-moutain-stream-in-the-middle-of-nowhere crystal clear. Just for one example, a meta analysis published in the journal Vaccine in 2014 looked at studies involving over a million children. The data revealed no relationship between vaccination and autism. None. Nada.

Vaccines, you see, do not cause autism. And actually, it’s about time we stopped wasting precious resources proving that over and over and over and over again and instead focused on what does cause autism, because that would be a question worth answering.

Infection rates dropped enormously in the US after the measles vaccination was introduced.

Infection rates dropped enormously in the US after the measles vaccination was introduced.

Anti-vaxxers will often repeatedly talk about mercury in vaccines. There’s mercury in vaccines, they’ll say, and that’s nasty stuff, so even if we haven’t proved it yet, they must be causing something bad. One problem there: there isn’t any mercury in vaccines. There’s a preservative called thimerosal (or thiomersal) in some flu vaccines – which are not the ones usually given to children – but thimerosal is no more mercury than salt is chlorine.

The anti-vax crowd get whackier after this. Some of them will tell you that vaccinations don’t, in fact, protect against against disease at all – despite huge evidence to the contrary (see also here), not to mention the simple fact that many of our grandparents and even parents remember these diseases, and their complications, as horribly commonplace.

Anti-vaxxers often state that deaths from these diseases were dropping before the vaccines were introduced. This is true. Deaths did drop, because medical science was developing rapidly. A measles patient receiving medical care is, indeed, less likely to die than one left to her own devices. If I may say so, duh.

What vaccines did is to massively reduce infection rates. But just to state the obvious: if people don’t catch a disease, they also can’t die from it.

In short, if an anti-vaxxer shows you a graph, it’s smart to check to the axes labels.

After that they get really loony, and some of them will even tell you things such as smallpox wasn’t eradicated, it was just renamed acne. Or polio has been reclassified as Guillain-Barré syndrome. These ideas are so utterly ridiculous they don’t even deserve rebuke.

This has started up again in the last few days, particularly in the UK, because of the nasty deposit of conspiracy crap that is the film Vaxxed. It’s available online, but I shall not be linking to it here.

The film claims to reveal a massive cover-up at the Centre for Disease Control (the CDC) in America, and evidence that vaccines are generally evil and cause all manner of heinous negative health outcomes. Very little of it is true, and where a tiny nugget of true fact has been included it’s been so beaten and manipulated as to have lost all of its original meaning. There’s an excellent piece about it on Skeptical Raptor website, which I recommend reading before you google the term “vaxxed”. Consider it a sort of inoculation against the nonsense, if you like (hoho).

A Guardian article from 2010 reports on Wakefield.

A Guardian article from 2010 (click for link).

The main brain behind the film is Mr Andrew Wakefield, a former British doctor who was struck off the General Medical Council in 2010, when the GMC said he had acted “dishonestly and irresponsibly.” Wakefield was, it turned out, trying to patent his own measles vaccine. In an effort to further his own aims, he set out to discredit the widely-used MMR (measles, mumps and rubella vaccine) by fabricating results and, in particular, suggesting a link between the MMR and autism. He denied all this, of course, but a libel judge disagreed.

Wakefield is still pushing his message. He is not a particularly nice individual. Listen to him in this video clip, for example, where he responds to Bill Gates comment, made in 2015, that he (Gates) fears a pandemic could wipe out humanity in his lifetime. Actually, I’ll save you the trouble:

“Ho Chi Minh City, you may have seen this, an outbreak of [laughs] the plague in Ho Chi Minh City. The outbreak that they were not prepared for, they never prepared for, and that is the number of children with autism in Ho Chi Minh City has increased by nearly one hundred and sixty times over eight years. So, Bill, just for your edification, the plague that you’re talking about, the next plague, the next epidemic, it’s already here. It’s already here.”

Yes, you heard that right, according to Wakefield autism is a “plague”. Anyone reading this with an autism diagnosis? You have the plague. Nice, huh?

Andrew Wakefield describes autism as a "plague".

Andrew Wakefield describes autism as a “plague”.

For the record, the number of autism diagnoses in Ho Chi Minh has increased sharply over recent years, but this is may well be – as often turns out to be the case – largely due to to better diagnosis. Certainly there’s absolutely no suggestion that it’s linked to the introduction of a vaccine or vaccines. There might be an environmental factor – some sort of pollutant perhaps – but no one is certain at the moment. (To repeat myself: perhaps if we stopped wasting time endlessly disproving the link between vaccines and autism, we’d have a better idea.)

By the way, the woman in that video clip is Polly Tommey. She has an autistic son who’s now in his twenties. Back in 2010 she chose to try and raise awareness of autism by posing in a Wonderbra-style advert, and these days she follows the campaign trail with Wakefield, repeating the message that they “will win”. What exactly they’re going to win isn’t entirely clear. Would preventing vaccination, at the cost of many lives, really be a win?

Vaxxed was due to be shown at the Curzon cinema in Soho, London on Valentine’s Day. It was pulled after the cinema realised what the film was – they had merely leased their premises to private individuals and only realised what was going on when a number of science advocates started complaining.

In a statement, a spokesperson for Curzon Cinemas said:

“We do not wish to profit from a film that has demonstrably caused great distress.”

The heyevent.uk page on Vaxxed, explaining that the location will be "annnounced" two hours before the screening.

The heyevent.uk page on Vaxxed explains that the location will be “annnounced” two hours before the screening.

Tommey was predictably unimpressed by this outcome, which she blamed on “our little five trolls in England,” saying “Britain being who they are, being big wussy pussies, just strike it off.”

Unfortunately, the cancellation turned out to be less of a victory than it first appeared. The anti-vaxx crowd then set out to find a new venue. And this time, they kept it quiet. There are many, many places that will rent you a space to screen a film, and I’ll wager that few of them really check the nature of that film. So, the anti-vaxxers correctly reasoned, if we don’t tell people where it is, no one will be able to stop us. People who had previously bought tickets were told it would be in “Central London”, and that the venue would be revealed two hours before the show.

And so, it happened. At Regent’s University London, a private university which was, incidentally, recently identified as the most expensive place to study in the UK.

In hindsight, this might actually have been worse than a screening at an independent cinema. Dodgy film in a cinema – so what? “Official” screening at a university with Q&A sessions afterwards? Hm, sounds important and… academic. The press, naturally, made the most of it, with headlines such as “Disgraced anti‑MMR vaccine doctor Andrew Wakefield gets invitation to university in London.” Sure, the first line of the actual article says the university has been criticised, but who actually reads beyond the headlines these days? Sounds like he’s being taken seriously, doesn’t it?

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Regent’s University’s response on Twitter on February 15th

Regent’s University responded pretty quickly to say that they hadn’t known what the film was, that they didn’t endorse its views, and that they would be revetting all their clients.

This provoked lots of complaints about freedom of speech, because many people seem to be under the misapprehension that freedom of speech means that any and all organisations and venues have a duty to allow them to repeat their nonsense. This is not what freedom of speech means. Freedom of speech means you can’t be chucked in prison for saying a thing (with some exceptions). It does NOT mean that everyone has to listen to you, or that you can say your thing wherever and whenever you like, whether the place renting you the space likes it or not.

More alarming still was the Q&A session at the end of the screening of Vaxxed. I watched some of it (one for the team, you’re welcome). There was much talk of “getting the message out there”, “sowing the seeds”, “people have to hear the message x times before they’ll start to accept it” and so on. In short, if you didn’t know it was all about vaccines it would start to sound an awful lot like…. well, at best a religion, and at worst a cult.

Wakefield was also asked if he would ever get his name cleared. This was his response:

Wakefield speaking at the end of the Vaxxed screening.

Wakefield speaking at the end of the Vaxxed screening.

“Well, cleared by whom? Here’s a… it’s a really important… cleared by whom? Do I want to be part of the medical profession again? [muttering from the audience] Do I want to be exonerated by the General Medical Council? Do I want to pay them an annual retainer fee? To be part of… Do I really? Is that… that takes time and effort. What is more important? Making films like this? Or trying to clear my name? [applause]

Hang on. If he really cared about getting the science right, about doing the right thing by patients, wouldn’t getting his name cleared and being reinstated as a medical doctor be of utmost importance? If he’s right about vaccines, particularly the MMR vaccine, and if he truly wants to prove it for the good of humanity, what better way than to be exonerated?

But as he says, “that takes time and effort.” What he doesn’t add, of course, is that making films like Vaxxed, travelling around the world spreading his message and hobnobbing with Donald Trump, almost certainly makes him a lot more money than being a doctor ever did. And I’ll bet it’s more fun. Why would he go back to the long hours and hard work that being a regular old doctor entails?

Wakefield is playing an extremely unpleasant and disingenuous game. The really worrying thing is that he and other anti-vaccination campaigners might be gaining ground. Robert F. Kennedy Jr. and Robert De Niro recently announced a $100,000 “challenge” to prove the safety of thimerosal vaccines. Thimerosal has already been extensively investigated – no evidence has ever been found that its inclusion in vaccines causes neurological effects, but anyway, it’s only in a few flu vaccines. Of course, the implication is that all vaccines are unsafe and that no one can prove otherwise – and now those headlines are out there, and that seed has been planted, will people really read further into it? Or will they just decide to skip the visit to the doctor?

The consequences of that are potentially serious. A mumps outbreak was reported in Washington State a week ago, and cases of mumps and measles have also just been reported in Salt Lake County. Last autumn the Guardian reported that the proportion of under-twos receiving their first dose of the MMR vaccine had fallen for the third consecutive year, and there were several reports of measles outbreaks in the UK. Flu outbreaks are also a real concern: years of hearing the phrase “mild flu-like symptoms” have created the misconception that influenza itself is a mild disease. It is not. There have been over 100 deaths from flu in Germany this year alone. People in Germany have access to good healthcare. People are still dying.

Outbreaks put everyone at risk: vaccination is effective, but nothing is 100% effective. In the midst of a full outbreak, even the vaccinated are at risk of catching the disease, and of course, those who are too young to receive the vaccine, or who can’t have it because of a genuine allergy, or because they’re immunocompromised, will be in real trouble. Let’s not forget: measles in particular is a disease with a host of horrible complications, not to mention the potential to reduce a person’s previously acquired immunity to other diseases.

Do we really want to see measles and mumps come back? Really? Because that will ultimately be the result of all of this.

And unfortunately, Captain Birk and Mr Spuck aren’t actually there to fix this mess for us. We need to see sense ourselves.


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The cold cure that’s 5000 years old

Could we just remove the front of my face? I think it'd be less painful....

Could we just remove the front of my face? I think it’d be less painful….

A couple of days ago I was struck down with a sinus infection. This is something I thought I’d had before, but it turns out that what I’d actually had before was an uncomfortably stuffy nose. Whereas this, on the other hand, was the sensation that someone had put my forehead in a vice and was inflating my eyeballs with a bicycle pump.

I explained this to the doctor. He nodded sympathetically and suggested a drug that’s been used, in one form or another, for five thousand years.

If you’re new to this blog, you might be wondering at this point whether, when I say ‘doctor’ I actually mean ‘naturopath’ (or some other thing that translates as ‘not a doctor’). But, no, this was a properly qualified member of the medical profession. Well, I hope he is. I mean, I haven’t looked him up on the General Medical Council’s list. I assume my surgery did that. I’m sure they did. Anyway….

207px-(+)-Pseudoephedrin

Pseudoephedrine

What was this mysterious, ancient medicine? It was pseudoephedrine, otherwise known (in the UK anyway) by the brand name Sudafed®.

It’s a drug many of us have probably taken to help with cold symptoms, and not given much thought to, but it’s actually got a pretty interesting story.

Pseudoephedrine falls under the class of amphetamines. The ‘amine’ bit of that word refers to the NH group (or it might be NH2, or even just N) and, being one of the fundamental bits in proteins, it turns up in lots of biologically active molecules. It’s in paracetamol (acetaminophen) for example, and antihistamine drugs used to treat allergies, as well as many molecules that occur naturally in the body, such as dopamine and adrenaline (epinephrine).

It’s also there in methamphetamine (commonly known as ‘crystal meth’ or just ‘meth’). In fact, pseudoephedrine and methamphetamine are chemically similar, and the latter can be synthesised from the former (I’m not recommending any of my readers try this; it’s very much frowned upon from a legal point of view). For this reason, the sale of pseudoephedrine is tightly regulated; in the UK you can only buy it over the counter in a licensed pharmacy, and then only in small blister packs. (Cold medications that you can pick up from the shelf usually contain the far less effective phenylephrine.)

800px-Ephedra_sinica_alexlomas

The Ephedra sinica plant

Where does it come from? These days, pseudoephedrine is made in a three-step process, the first of which involves yeast fermentation, but it was first isolated from plants, in particular Ephedra sinica, also known as Chinese ephedra or Ma Huang.

This is where the five thousand years comes in, because these plants have been used in Chinese medicine for millennia. In fact, Ephedra is one of the oldest known medicines. It’s described in the legendary Chinese pharmacopoeia Pen-tsao Kang-mu, and became a common part of Chinese prescriptions to treat cold symptoms, fevers and asthma.

The first substance in Ephedra plants to be used in western medicine was Ephedrine. It was isolated in 1885 by a Japanese chemist called Nagai Nagayoshi, but it was then rather forgotten about until 1920s, when it was rediscovered and became a popular treatment for asthma.

In those days, steroid inhalers had yet to be developed, and the standard treatment for asthma was adrenaline. This was problematic, because adrenaline isn’t orally stable: it had to be injected. Ephedrine, by contrast, would work if swallowed as a pill, making it much easier to use.

Ephedrine_enantiomers

Ephedrine is made up of a mixture of these two mirror-image molecules

Unfortunately, ephedrine had rather unpleasant side-effects. It caused raised blood pressure, and then there were a number of other potential problems such as dizziness, trembling, headache, irregular heartbeat and even, in some cases, heart attack and stroke. Worth the risk perhaps, if you’re in the middle of a life-threatening asthma attack, but not something you’d want to use routinely.

The story goes (although I haven’t been able to verify this by finding, say, a recorded study) that when the use of the whole Ephedra plant as a treatment was compared to the use of pure ephedrine, people noticed that the side-effects were much less severe, even though the whole plant still appeared to be an effective treatment. This caused researchers to wonder whether there was some other substance in Ephedra that had subtly different effects on the body.

Whether this observation was really made or not, it turned out there was another active molecule in the Ephedra plant. It was first separated from ephedrine in in 1927, and was given the name pseudoephedrine, literally ‘false ephedrine’. Ephedrine and pseudoephedrine are structural isomers: they have the same number and type of atoms, ordered slightly differently. This is a common theme in medicinal chemistry: switching just a couple of atoms around can make big differences to the way the human body reacts to drugs.

Like ephedrine, pseudoephedrine was an effective bronchodilator and vasoconstrictor (causing blood vessels to shrink), but its effects were less dramatic, which made it a lot safer. It doesn’t raise blood pressure nearly as much, and is far less likely to cause something really nasty like a heart attack. That said, it’s not side-effect free, and it should go without saying that anyone with an existing medical condition should speak to their doctor before using it. Likewise, don’t go messing about with Ephedra plants.

Vasoconstriction is why pseudoephedrine such a good decongestant. Less fluid leaves the shrunken blood vessels and therefore less fluid enters the throat, nose and sinus linings. This reduces inflammation mucus production, and the incessant pounding of a sinus headache eases up a bit.

Of course, pseudoephedrine doesn’t somehow know to restrict itself to your nose and lungs. Blood vessels throughout the body are affected. This can be useful – for example, pseudoephedrine can help to treat ear infections – but it can also result in other, less desirable effects. In particular, pseudoephedrine suppresses breast-milk production, and for this reason shouldn’t be used by new mothers trying to establish breastfeeding. It might also interfere with mucus membranes in the vagina, potentially causing a small reduction in fertility and, not surprisingly, a substance which is a vasoconstrictor can also aggravate erectile dysfunction. Basically, if you’re trying to make a baby this might be one to avoid, although if you’re stuffed up with a cold you might not feel like it anyway, so perhaps it doesn’t matter.

Anyway, I know what you’re all desperately wondering: But, Chronicle Flask, did it sort out your sinus infection?!

dara

“Science knows it doesn’t know everything; otherwise, it’d stop.”

Well, actually, I’m relieved to report that after taking three doses of pseudoephedrine twice a day for a couple of days the pain has eased up considerably. Of course, there’s nothing antiviral (or antibacterial) in this medicine, but it would appear that my immune system managed to take care of the infection for me, once the inflammation was reduced and the excess fluid which was causing the pressure was able to (yuck) drain away.

To quote the comedian Dara O’Briain:
“‘Oh, herbal medicine’s been around for thousands of years!’ Indeed it has, and then we tested it all, and the stuff that worked became ‘medicine’.”


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Homeopathy: a drop in the ocean?

HomeopathicCartoonAs a skeptical chemist I have, until now, avoided the topic of homeopathy.  It felt a bit obvious, rather like shooting fish in a barrel.  Hasn’t everyone and his sister written an article about it at some point?  There’s the brilliant 10:23 campaign on the subject, and the comedians Mitchell and Webb even wrote a fabulously funny sketch on the topic (do watch it if you haven’t, I particularly love the idea of homeopathic lager).  How much more mainstream can you get?  Surely everyone knows it’s a load of old nonsense by now?

And yet, and yet… I still meet people that don’t know what it is, or who are a bit confused about it.  Many don’t know the difference between herbal remedies and homeopathy.  Many think they know someone who’s used it and it’s worked, or have used it themselves and felt that it helped them.

Worse, the NHS, despite admitting outright that, “homeopathic remedies perform no better than placebos, and that the principles on which homeopathy is based are ‘scientifically implausible” still spends money on it, going on to say on the very same web page that “there are several NHS homeopathic hospitals and some GP practices also offer homeopathic treatment.”  There are widely divergent figures on exactly how much the NHS spends on this treatment which they fully admit does not work, but there’s general agreement that it’s in the millions.  A fullfact.org article written in 2010 concluded that it was £12 million from 2005-8, which didn’t include the £20 million spent refurbishing the Royal London homeopathic hospital from 2002 to 2005.  More recently a Daily Mail article (yes, yes, I know) claimed it was £4 million a year.

In a way, does it matter?  It may be a tiny proportion of the NHS’s total £108.9 billion budget, but it’s still millions of pounds of public money.  For something that doesn’t work.

Ok, but what is it?  Well firstly let’s briefly talk about ‘mainstream’ medicine.  Also called conventional medicine, allopathic medicine, orthodox medicine or Western medicine, it’s the system by which trained professionals (doctors, nurses, pharmacists etc) treat diseases and their symptoms using tested drugs.  And make no mistake, mainstream drugs are tested.  Different countries have different regulations, but in the UK clinical trials involve at least three phases and take ten to fifteen years or even more.

Homeopathic treatments don’t have to go through this testing.  And unlike conventional doctors, who have to complete five years of study followed by further years of foundation training and yet more studying, there is no regulation of homeopathic practitioners in the UK.  Now, that ought to give anyone pause for thought.

Secondly, all drugs that actually work have side effects; effects that are secondary to the intended ones.  All of them.  There’s no avoiding it; there’s ‘no effect without side effects’.  You may not experience them personally, but someone somewhere almost certainly will.  Much of medicine is about balancing side effects against positive effects, and a lot of the time it comes down to how severe and life-threatening the disease being treated is.  If you have a bit of a cold, you’re probably happy to take some paracetamol which, when taken at the proper dose, has ‘as rash’ listed as its only side-effect.

But since the odds are very good that you’re going to recover from your cold whether you treat it or not you wouldn’t, on the other hand, want to take something that might have serious side effects like the anti-viral Tamiflu (headaches, nausea, cough, vomiting, sleeping problems, indigestion, pain, tiredness, vertigo… and that’s just some of them).  However, if you genuinely have flu (real flu, not “I’ve got a nasty cold but I’m calling it flu so that I sound like less of a skiver”) then Tamiflu might be appropriate, because real flu can be genuinely life-threatening.

HomeopathyWhy is this relevant to a discussion about homeopathy?  Because homeopathic treatments don’t have side-effects (at least, not any directly related to the pills and potions themselves).  Homeopaths are generally quite keen to tell you this.  But it means that the treatments are ineffective. There’s no getting around this I’m afraid.  You can’t have your cake and eat it, even if you dilute it by a factor of 1060.

Speaking of dilutions…  Now, I’m not about to go into a huge amount of detail about the history and reasoning behind homeopathy because, firstly, other people have already done an excellent job of that, secondly I always worry that it starts to sound alarmingly plausible if you’re not very careful and thirdly, a summary ought to be much more potent than a full description (this little witticism will make sense in a minute).

Certain substances, poisons generally, cause nasty symptoms.  Homeopaths believe that if you take very, very tiny amounts of those substances they’ll do the opposite and cure those symptoms when they’ve been caused by an illness.  For example, arsenic causes headaches, nausea and diarrhoea.  So logically (for a given value of ‘logic’) at homeopathic doses it’s used to treat digestive disorders and food poisoning.  These tiny amounts are achieved by successive dilutions: you add one drop of a substance to ninety-nine drops of water, and then you take one drop of that mixture and add it to ninety-nine more drops of water, and then you take one drop of that and….

…You keep going until you’ve done it at least six times.  Remember each dilution is a factor of one hundred.  The first time it’s done you get a solution of 0.01%.  By the time the procedure’s been followed six times, it’s 0.000 000 000 1%.  This is called 6C.  Homeopaths believe that more dilute solutions are more potent, that is they’ll be even better at treating the illness than something more concentrated.

0004908_nelsons-bryonia-30c-homeopathic-remedy_300In fact, quite a lot of remedies are sold as 30C.  That’s 0.000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 1%

Let’s attempt to put that in context.  Every year Cambridge University’s Chemistry department holds the Cambridge Chemistry Challenge (try saying that six times fast) and in 2012 there were some rather lovely questions involving homeopathy in the paper.  Here are a few choice morsels:

One question asked entrants to calculate the mass of arsenic oxide in 100 ml (a small amount, but still about four times greater than the volumes that are usually sold) of a 30C homeopathic remedy.  The answer was 2.06 x 10-30 grams.  That’s a thousand times less than the mass of a single proton.  A drop in the ocean isn’t the half of it.  Not only is there not even one molecule of the original substance in there, the dilutions have wiped out even the possibility of a sub-atomic particle.

6a00d83451df0c69e200e54f9413f98833-800wiThen they were asked to work out the amount of the remedy someone would need to take to experience a fatal dose, and express the answer as a fraction of the volume of the Earth.  The answer?  4500 times the volume of the Earth.  Probably no need for those “in case of accidental overdose contact a healthcare practitioner” warnings, then.

Finally, how many bottles of the solution would you need to buy to stand a chance of obtaining one atom of arsenic?  The answer: 285 million bottles.

So let’s be clear, homeopathic remedies have no active ingredient.  Nil.  Nothing,  Nada.

“Ah,” say the homeopaths, “we accept that.  That’s not the point.  The water ‘remembers’ the original chemical; the water molecules retain a ‘memory’ of that substance and it’s that memory that has the effect”.

At this point people who actually know some science start tearing their hair out (by the way, apparently fluoric acid, i.e. HF, is a recommended homeopathic treatment for hair loss – good job it is diluted else it might eat through the glass bottle).

Just think about it for a few seconds.  If it were true that water retains a memory of the substances that have been dissolved in it, and that memory was so powerful that it could have a real, physiological, effect on the body, then we would be constantly bombarded with ‘treatments’ every single time we drank a glass of water.  You know that water that comes out of your tap?  Well, sorry to be blunt about this, but it went through a few other people before it got to your tap, picking up all sorts of substances on the way.  Your local water company purified it, and in the process almost certainly added coagulants to precipitate out impurities.  These are then removed of course (that’s the point) but if what the homeopaths suggest is right (which it’s not) your water would ‘remember’ them.  Lead pipes would be the least of your worries.

From here the theories get increasingly outlandish.  Next stop, ‘transference’.  This is the idea that remedies can affect living organisms from a distance.  Yup.  Basically a practitioner can call someone on the phone and proceed to diagnose, and treat, them from miles away, without them having to actually swallow a thing.  Oh yes, and also water placed next to a homeopathic remedy (which is also just water, in case I need to say it again) can take on characteristics of the remedy.

Photo 13-06-2013 09 06 54 PMNow, if this were true the world simply wouldn’t work the way we know it does.  You’d be exposed every time you walked past the Alternative Remedy section in a shop.  Humans have really quite a lot of water in them; if anything like this actually happened, you could ‘catch’ antibiotics from your friend who happened to be taking them, just by standing too close.  You wouldn’t need to clean your toilet, just leave the bleach bottle next to it and it ought to work by transference (many students have tried this, it really doesn’t work).

The homeopaths will cry that I’m wilfully misunderstanding their methods, because I’ve forgotten to mention ‘potentization’.  Oh yes, allow me to explain: when you prepare a homeopathic remedy you have to shake or tap the preparation at each stage – sometimes with a particular object (a magic wand, perhaps) – otherwise it doesn’t work.  It’s not just the dilution, it’s the special tapping that does the trick, because it somehow allows the water molecules to remember the energy signature of the molecules of ‘active’ ingredient.

Next time someone claims homeopathy works, ask them if they believe in magic.  There really is very little difference.

At this point though homeopaths resort to a few final bits of misdirection and sleight of hand.  They claim that everyone who casts doubt over homeopathy is in the thrall of ‘Big Pharma‘.  They say that the big pharmaceutical companies – whom they imply control the world, possibly from a giant hollowed-out volcano somewhere – deliberately discredit homeopathy because they have a lot to lose if people use it instead of conventional (they tend to use the term ‘allopathic’) medicine.

This neatly sidesteps the fact that homeopaths have an awful lot to lose if people stop buying their pills and potions, and especially in the UK if the NHS stop funding it.  In fact, I suspect they have a lot more to lose since pharmaceutical companies, for all their faults, are required by law to prove that their drugs actually do something.

And finally homeopaths will tell you that allopathic medicines have killed millions of people, whereas homeopathy has never killed anyone.  Hm.  It’s true that people die from negative drug reactions.  It’s also true that sick people sometimes die.  Occasionally it’s difficult to say whether a person would have died sooner with or without drug intervention.  But for most people conventional drugs are far more likely to keep them safe and well than kill them.

sopHomeopathy on the other hand… well it’s true the remedies themselves won’t kill you.  A little bit of sugar and water never killed anyone.  But, sadly, there are people who don’t seek conventional treatment because they believe what a homeopath tells them.  Sometimes those people leave it too late, and sometimes they die when their life might have been saved.  Even worse, sometimes those people are parents, and they end up making bad decisions about their child’s treatment.  If you doubt me, there’s a whole list of tragic stories on the whatstheharm website.

Sometimes homeopathy does appear to work, but that’s been shown time and time again to be a placebo effect.  Now, I think that the placebo effect is cool.  I mean, it’s really awesome.  Basically, if you believe you’ll feel better, you do – at least sometimes.  People have even debated whether this can work in animals (probably not, although owners and vets might think it’s working).  Personally, I think lots of research should be going on in the area of placebo, because it’s utterly fascinating.  But.  Here’s the thing: I used the words “feel better” back there very deliberately.  The placebo effect is great for things that have a level of subjectivity, such as pain management.  When people carry out objective measures, such as lung function for an asthmatic for example, there’s usually little improvement.  The placebo effect is highly unlikely to effectively treat diseases such as asthma, or diabetes, or cancer.

And that means homeopathy cannot treat those things either.  And people absolutely shouldn’t be allowed to tell ill, vulnerable people that it can.

I know there are some people who don’t trust the government, and who think it’s all run by nine foot tall lizards, but regardless I’m going to return to the Science and Technology Committee’s report:

Screen Shot 2013-06-13 at 22.53.02“the evidence base shows that homeopathy is not efficacious (that is, it does not work beyond the placebo effect) and that explanations for why homeopathy would work are scientifically implausible.”

and…

“The product labelling for homeopathic products under all current licensing schemes fails to inform the public that homeopathic products are sugar pills containing no active ingredients.”

Finally, ask yourself this: at a time when disabled people are facing cuts to their much-needed benefits, with many tragic stories of people being designated ‘fit for work’ when they really aren’t, is it right that millions of pounds are available for a ‘treatment’ which, at the risk of sounding like a stuck record, does not work?

And for the record, I have absolutely no affiliation whatsoever with any pharmaceutical company.  I am, however, more than happy to admit supporting campaigns such as 10:23, because there really is ‘nothing in it’.

—-

Late addendum: I have just been reminded (thank you @Sci_McInnes) that of course our Health Secretary, Jeremy Hunt (the one made famous by James Naughtie’s delightful slip of the tongue) is a supporter of homeopathy.  Yes, the person that is effectively in charge of the NHS believes that tapping water in a special way turns it into an effective medicine, despite the evidence of the Science and Technology Committee.  If you weren’t cross about it before, you really, really should be now.