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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Realgar: don’t drink the AsS wine

I was planning a lesson on empirical formulas recently and, bored with the usual well-worn examples (hydrogen peroxide, ethene, ethanoic acid, yawn), went hunting for some unusual chemicals. So it was that I came across a substance with the molecular formula As4S4, which appealed to my immature side since – fellow chemists will be ahead of me here – it has the empirical formula of AsS. Heh.

Realgar crystals

Realgar crystals

Anyway, turns out this stuff is interesting for more than just spelling a word that means bottom in American English. This particular form of arsenic sulfide is more commonly known as realgar, and for starters it’s very pretty: check out those lovely red crystals. In fact its other names are ‘ruby sulfur’ and ‘ruby of arsenic’.

It often turns up in the vicinity of other mineral deposits, such as lead, silver and gold ores, and has a long list of uses. It’s a source of arsenic, which is used to make gallium arsenide (formula GaAs – not quite as good, but credit for trying), an important semiconductor used in the production of integrated circuits, solar cells, and other electronics-y stuff.

Perhaps more interestingly, realgar used to be used by firework manufacturers to produce, somewhat counterintuitively, the colour white. It’s still used to make a contact explosive (who doesn’t love substances that spontaneously explode when touched?) At least, so says Wikipedia and numerous other pages that appear to have copied Wikipedia. I actually can’t find any more information on the chemistry of this particular substance – named as ‘red explosive’ – and if anyone knows I’d love to hear more.

What else? The Romans considered realgar valuable and used to trade it for use as a red paint pigment and in medicines. Which is ironic since, as a source of arsenic, it’s toxic and carcinogenic. Medieval Spaniards used it to kill rats, as did 16th century Brits. The Chinese call it xionghuang 雄黃, which translates to ‘masculine yellow’ (the related mineral orpiment, As2S3, is called cihuang 雌黃, or ‘feminine yellow’*) and used to use it as a handy insect- and snake-repellent. It turns up in traditional Chinese medicine, which isn’t particularly reassuring. Specifically, realgar is often added to treatments to reduce fever, inflammation, treat ulcers and calm skin conditions. Beware.

Realgar wine

It’s also mixed with rice wine to make something called ‘realgar wine’ which is, rather alarmingly, still consumed during Duanwu Festival, also known as the Dragon Boat Festival, to ward off evil. And it’s not just adults: children’s foreheads and limbs are also traditionally painted with the stuff. Yikes. Apparently this practice started because Duanwu falls just before midsummer, and the hot weather used to precipitate the rampant spread of various diseases. Realgar was believed to be a universal antidote to poisons, and was great at warding off insects and other bothersome creatures: why not disease as well? It would appear that the use of realgar has declined somewhat, now that people have a better idea of the potential dangers. I hunted around and couldn’t find realgar wine explicitly available for sale anywhere, although it’s not difficult to find realgar itself. Be careful: even a one-off exposure can cause kidney failure.

So there we go: that stuff with the empirical formula AsS that’s traditionally used to ward off disease turns out to do the exact opposite, and cause illness. Still, the red crystals are very pretty. And if you do know anything about ‘red explosive’, please comment!

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* Err, I hope. I’ve copy-pasted those symbols. Apologies if they actually say purple tadpole penis or something.