Thursday, 8 September 2011

Traditional Chinese Ephedrine

You don't find ephedrine in many medicines today, although you will still find plenty of cold remedies that contain its alter ego pseudoephedrine (a stereoisomer of ephedrine). In pharmacological terms, the two drugs differ mainly in potency, with ephedrine being the more potent. From its rediscovery in late 1920s until the 1960s, ephedrine was a common drug for the treatment of asthma and rhinitis. Ephedrine acts in a similar way to cocaine and amphetamine, by increasing noradrenaline release from sympathetic nerves surrounding blood vessels and subsequently restricting blood flow to the mucosa of the nose and airways (described in detail here). In fact, the histories of these three drugs are intertwined, as we shall see.

Ma Huang
Chinese folk medicine has used Ma Huang [Ephedra sinica] for centuries. Emperor Sheng Lung reported its effects – along with the entire Chinese pharmacopoeia of the day – in 2750 BC. It wasn't until 1887, that the Japanese scientist Nagayoshi Nagai isolated, identified and named the principle active ingredient:  ephedrine. Early experiments with ephedrine determined that it was a fairly toxic compound and it was largely ignored until Takahashi and Miura described its mydriatic effect on the eye (opening the pupil to allow examination) five years later. It was marketed briefly in Europe for this use, although physicians of the day noted that it caused local irritation of the eye and it never really took off. Chemists tinkered with synthesising ephedrine over the next 20 years or so, establishing that there was a mirror image molecule (stereoisomer) - pseudoephedrine – also present, but in terms of clinical use ephedrine faded away.

Apparently unaware of Takahashi and Miura's work, Peking-based scientists Chen and Schmidt rediscovered ephedrine, isolating it once more from Ma Huang, and described its physiological effects in considerable detail in 1927. They noted that the drug increased blood pressure and correctly speculated that ephedrine interfered with the release of neurotransmitter from sympathetic nerves to cause a contractile effect on blood vessels and increase in heart rate. What excited them was the duration of action. Until this time adrenaline had been used to raise blood pressure in situations such as shock or during surgery. Adrenaline was also used to treat acute asthma attacks, and most physicians at the time would probably have ascribed its action to contraction of blood vessels in the airway mucosa, an idea which led to a brief flirtation with cocaine as an alternative. Ephedrine surpassed them both. Indeed its duration of action was an important selling point for Borroughs Wellcome & Company:

From BW&Co catalogue (1928). Vertical axis is blood pressure, horizontal axis is time.
Another selling point was that unlike adrenaline, which has to be injected, ephedrine is active orally. While adrenaline was used acutely during crises, ephedrine was generally prescribed to be taken daily to prevent or blunt attacks. As is was considered to be equally effective at reducing swelling in the nose, as well as the airways in the lung, ephedrine became a block buster for treating runny noses and asthmatics alike. Compared with cocaine, it had less of an effect (and a less complex effect) on the central nervous system. Although mild central nervous system effects were the main side effect noticed by patients, nothing available at the time could compete with ephedrine.

The blockbuster status that ephedrine achieved encouraged chemists to develop competitor drugs. Amphetamine was one such great hope, but its strange course took it into the murky world of psychiatry. Pseudoephedrine, the poor cousin finally came into use as a nasal decongestant in the 1960s as ephedrine was phased out for being just a bit too potent. And in many countries there are calls to ban the sale of pseudoephedrine, because it is too easy to convert into methamphetamine. Too potent for a cold and flu remedy, and usurped by the true bronchodilators (beta-agonists, which relax the muscles surrounding airways) in the 1960s, ephedrine slowly faded away.

There's another story in the history of ephedrine that I'd overlooked by limiting my perspective to the UK. In the USA, ephedrine was a controlled drug from 1938 onwards. However, the Dietary Supplement Health and Education Act (1994) allowed the herbal preparation of Ephedra to be marketed - in a sense - as food. This supposedly safe, ‘herbal’ preparation contained, of course, ephedrine and pseudoephedrine and was as just as dangerous as any herbal product (e.g. opium). However, the general public on the whole perceive ‘herbal’ to imply ‘natural’, and therefore ‘harmless’. The purveyors of such products became very rich and powerful lobby groups overnight and resisted all sensible attempts at regulation of their amphetamine-like product. As you might predict in an unregulated market, supplement manufacturers began a programme of outrageous exploitation of consumers. Ephedra-containing supplements were even advertised on television channels such as MTV in a manner directed towards the adolescent market (e.g. as Herbal Ecstasy). Meanwhile, the reports of adverse effects of the supplements (which predictably matched those for ephedrine and pseudoephedrine) started to accumulate. However, under the new act, it became much more difficult for the FDA to ban Ephedra in supplements, and the herbal industry fought hard to keep their multi-billion dollar industry profitable. Welcome to Big Herbal – dealing drugs as food to evade the law.

Ephedra was promoted for two reasons. Firstly, amphetamine-like compounds raise body temperature and hence make users burn surplus energy stores and lose weight. History is littered with illegal diet pills containing amphetamine and other stimulants for the same reason. Secondly, users - predictably - feel more energetic, which appealed to athletes of all walks of life. The combined effects probably did result in weight loss, but no improvement in athletic performance was ever reported. Ephedra was marketed under names such as Super-Shape Fast, Ripped Force, Herbalife’s Thermojetics, Metabolife 356 amongst others, appealing to a wide audience. Roughly 80% of users were attracted by the supposed weight loss properties of Ephedra, the remainder were athletes and bodybuilders. While the FDA and other groups tried to highlight the dangers of taking Ephedra as a dietary supplement, the herbal industry fought very hard for consumer rights to take what they sold as a ‘natural’ supplement.  By 1999, annual sales of ephedra-containing supplements soared to 425 million units.

As a compromise, in 1997 the FDA proposed a labelling rule to force manufacturers to indicate to purchasers what kind of intake of ephedra was reasonably safe and what risks (including stroke, heart attacks and death; as with cocaine or amphetamine) were associated with frequent use or over-ingestion. Predictably, the then burgeoning supplements industry vociferously opposed any such regulation. They were supported by their customers, many sporting bodies and health magazines. Furthermore, they were feeding money into political parties at the time. As the San Francisco Chronicle reported around the time that Assemblywoman Susan Davis proposed that the FDA suggestion be made into local law:
Haller [a medical toxicologist] recommended that the substance be classified as a drug rather than as a dietary supplement, and that legislators consider requiring consumers to get a prescription before buying the product.
Davis' legislation does not go that far. A legislative officer close to the ephedrine controversy said that it was a political impossibility.
"Given the power of the herbal lobby, we couldn't get the votes for prescription status", said the staffer.
Unsurprisingly, the law wasn’t passed. Neither was the Proposal to Amend the Convention on Psychotropic Substances Act of 1971 (2001), or the Ephedrine Alkaloid Consumer Protection Act (2001), or the Ephedra Public Protection Act (2003), or the Dietary Supplement Safety Act (2003) or indeed the Dietary Supplement Access and Awareness Act (2003).  But 2003 was the year that galvanised public opposition to the unregulated trade in Ephedra.  When the professional baseball pitcher Steve Bechler quite literally overheated (to a core temperature of 42 ºC/108 ºF) after taking Ephedra prior to a training session and subsequently died, the public began to question how this could have been allowed to happen, and the press saw a natural opportunity to print sensational headlines.  By 2004, the number of voluntary reports of adverse reactions to Ephedra-containing supplements had reached 18,000 and three-quarters of the public comments received (48,000) were in favour of a ban.  In April 2004, the FDA did just that, and despite a few attempted reinterpretations, Ephedra remains a banned substance for dietary supplements. 

There were probably some sensible people in the supplement industry in 1997.  They may have spoken of the long term benefits of a little regulation against the balanced cost of a probable, temporary loss of revenue.  If they’d been listened to at the time, Ephedra-containing supplements would probably still be on the shelves in health shops in America.That's quackery for you.

Wednesday, 15 June 2011

Creosote for a tickly cough.

If you look amongst the potions and remedies in any pharmacy, you’ll find a preparation for cough that contains guaifenesin.  Quite often this chemical is mixed with other dubiously-effective drugs as cough mixtures, in the hope that at least one component will do some good.  However, a recent meta-analysis suggests we have very little evidence that these products have any consistent effect in either reducing cough, or loosening phlegm. The history of guaifenesin and its grandfather, guaiacum, stretch back over half a millennium, and it’s quite surprising how many conditions this placebo has been thought to cure.  Let's start at the begining with syphilis.

The origins of syphilis have long been the subject of debate. Recent genetic analyses support the theory that Columbus brought syphilis back from the Caribbean in 1493. By 1509, the Spanish had also brought back the supposed cure, based on the folk remedy of the local people of San Domingo: the resin of from one of the more interesting indigenous trees (Guaiacum). Extracts of this resin entered European pharmacological lore and quickly replaced the previous poison for syphilis (mercury). Indeed, it wasn’t until the mid to late 19th century (over 400 years) that physicians began to doubt the efficacy of this remedy. Because syphilis could be confused with many other skin conditions at the time, the supposed efficacy of guaiacum probably stemmed from its placebo effect in self-resolving, non-syphilitic conditions:

"Yet those who most strongly believed in its efficacy were constrained to admit occasional failures; and on the other hand, we can now see that many conditions which guaiacum was supposed to cure probably did not belong to the venereal class, so that the drug acquired a celebrity it did not deserve"
-Philips (1874) [A materia medica]

Arthritis and gout
Around the same time that guaiacum was used for treating syphilis, we find references to the supposed efficacy of this extract on rheumatic conditions.  This additional use probably occurred to physicians because, if left to run rampant, syphilis can attack the bones, producing arthritis-like symptoms.  Since the advent of antibiotics, we don’t see this very often today. It is understandable then, that being unclear on the differences between conditions, 16th century physicians may have treated syphilitic arthritis, other arthritic conditions and gout all with guaiacum. Indeed, the rich playboys of the age might well have sexual and gastronomic appetites that led them to have syphilis and gout at the same time. King Charles V (1500-1558) was said to have taken guaiacum for his gout, putting its use in both syphilis and gout within the scope of half a century or less.   The use of guaiacum in arthritis, gout and poorly-defined rheumatisms persisted beyond the late 19th century and into the 20th century when it was finally debunked.

Wood creosote (not coal-tar creosote)
Creosote was first isolated from Beech wood by Baron Carl Ludwig Reichenbach in the 1830’s and found to have properties that helped skin wounds heal.  Indeed, Reichenbach's kreosote is an allusion to the flesh healing properties it was thought to possess. It was used extensively through the 19th Century as an antiseptic (it probably helped wounds heal by cleansing them of micro-organisms, preventing infection).  Later, as chemistry improved it became clear that wood creosote is, in fact, mostly (70% or more) guaiacol, which turned out to be the same main constituent of the crude extract of guaiacum that had been used for centuries. Chemistry was beginning to solve the mysteries of nature, and the use of magical Caribbean trees started to decline.

Tuberculosis (TB)
Continental physicians tinkered with raw creosote for as a treatment of TB from the 1830’s onwards, but this practice fell in and out of fashion over the next 50 years.  Interest in the UK was reinvigorated in the late 19th century by Coghill, who recommended using injected, purified guaiacol, suggesting that it kills the germs responsible for TB.  This supposed antiseptic property of guaiacol ensured its use in treating TB for several decades.  At the dawn of the second world war, Hale White’s Materia Medica finally concluded:

“These drugs [various salts of guaiacol] have been used for the same purposes as creosote in the treatment of pthisis [tuberculosis] and as intestinal antiseptics.  They are equally useless.”

While it was becoming clear that guaiacol is useless for treating TB, it remained in use as an “expectorant”. It seems likely that physicians clung to the idea that guaiacol was useful in treating TB, even if it didn’t kill the infective organisms themselves.  Perhaps they just couldn’t give up on a drug with such a long history.  Medicine is a culture, after all, not a set of rules that everybody follows. Canadian-based Eldon Boyd experimented with guaiacol and the recent synthetic modification – glycerol guaiacolate (later renamed guaifenesin) - on animals during the 1940s. His data showed that both drugs were effective in increasing secretions into the airways in laboratory animals, when high enough doses were given.  Guaifenesin took off from there.