Antimony in one form or another has been used in the treatment of disease for more than 3000 years. Egyptian papyri reveal that the naturally occurring mineral stibnite (black antimony sulphide) was given to patients to treat fevers and skin conditions. The Roman physician Dioscorides of Anazarba (southern Turkey), who lived in the second half of the first century ad, was also familiar with stibnite; which he called stibi and recommended it for skin complaints, ulcers, and burns, and that it was to be applied as an ointment mixed with wax. He also noted that stibnite could be reduced to the metal by heating on coals and that it melted like lead. Another advocate of antimony sulphide was Kalaf ibn-Abbas al-Zahrawi (d. 1013), who was known in Europe as Abulcasis. He was a distinguished doctor of Moorish Spain and aware that antimony's use was approved of by the Prophet himself, who recommended it for the treatment of diseases of the eye such as ophthalmia.
Antimony metal appeared in two guises in the Middle Ages: emetic cups and perpetual pills, the former to cure a hangover and overindulgence, the latter to cure constipation. At the end of an evening of eating and drinking to excess, some wine was left in a special goblet made of antimony to be drunk the following day, whereupon it would soon provoke vomiting and empty the stomach. Perpetual pills were small balls of antimony which were swallowed. These would irritate the gut thereby promoting it to action to eject the irritant. The pill was then retrieved from the expelled excrement, washed, and stored for further use. There are reports that such pills were highly effective and passed from generation to generation.
Antimony compounds really came into vogue in the 1500s when they were used to treat all kinds of ailments, but not all doctors believed in them. The so-called Antimony War broke out in the 1600s between empiricists, who followed the teaching of Paracelsus which recommended their use, and the traditional Galenists, who clung to the older ways advocated by the ancient Roman physician Galen. Paracelsus praised the use of antimonals and his favourite remedy was lilium, which consisted of an alcoholic solution of the nitrates and tartrates of antimony (4 parts), tin (1 part), and copper (1 part). This he advocated as a treatment for many complaints.
As new antimony compounds were prepared, they were experimented with by the growing number of empiricists. Nevertheless, the Faculty of
Physicians of Paris condemned the use of antimony treatments and succeeded in getting them severely restricted by a law of 1566, an Act that remained on the statute books of France for a century. Some states in Germany were equally convinced antimony should be banned, and from 1580 to 1655 all the graduates of the medical faculty of Heidelberg University were required to take an oath that they would never administer antimony (or mercury) to a patient.
Slowly the empiricists gained the upper hand and antimony medicaments were eventually being advocated by eminent doctors in the 1600s. They were supported by the writings of Oswald Croll (1580-1609) who wrote Basilica Chymica [Basilica of Chemistry], and this contained 23 recipes that used antimony. He was particularly impressed with antimony trichloride (SbCl3) which has a butter-like texture and indeed was called butter of antimony.* In water it reacts to form insoluble antimony oxide chloride (SbOCl) and this was how it was prescribed, otherwise it would have been too dangerous to use, even externally. The virtues of antimony were also popularized in a book The Triumphal Chariot of Antimony, published in 1604. While many of its recipes are obscure, it is possible to deduce the chemicals being talked about, such as glass of antimony, which is antimony oxide sulphide, and fixed antimony, which is antimony nitrate.
By the end of the 1600s there were more than a hundred remedies based on antimony compounds. Some physicians who produced antimony-based powders gave their names to the product. Victor Algarotti, a physician of Verona, Italy, who died in 1603, produced one that came to be known in England as Powder of Algaroth, and this was prescribed as an emetic. It was antimony oxychloride and taking it produced instant vomiting, which was seen as a way of expelling bad 'humours' from the body. Other patent medicines became even more popular such as the Earl of Warwick's powder, which appeared in 1620. It was concocted by Robert Dudley (1574-1649), who was the son of the famous Earl of Leicester, Queen Elizabeth I's favourite. (The Earl of Leicester married Dudley's mother only two days before his birth and later abandoned her, even denying that he had married her.) On
* Antimony trichloride is a solid crystalline material at low temperatures, but at ordinary temperatures it becomes a paste-like mass resembling butter; it melts at 73°C to form a yellow liquid that fumes in air. Until recently, vets used a solution of antimony trichloride dissolved in a solvent like alcohol or chloroform to de-horn calves, although by law it had to be applied within a week of their being born.
the death of the Earl, Dudley attempted to establish his legitimacy and so claim the titles and estate of his father, and when he failed to do this he emigrated to Florence where he converted to Roman Catholicism. There King Ferdinand II created him Earl of Warwick and the Pope ratified his title. Dudley died in 1649.
The Earl of Warwick's powder became internationally famous when it was used with astounding success to cure the 19-year-old King of France, Louis XIV, who fell ill with typhoid fever at Calais in 1657. From that time onwards it never looked back. Its use may have been banned by the Faculty of Physicians of Paris but they could hold out no longer and the law against antimony was repealed in 1666. Even so, it was fraught with danger and brought the medical profession a certain amount of censure. The French playwright Molière was convinced that the death of his only son was due to its careless administration and this is probably the reason why he never missed a chance to poke fun at doctors in his plays. His work La Malade Imaginaire [The Imaginary Illness], about a hypochondriac and the efforts to cure him, was a natural vehicle for comedy at the expense of the medical profession. Ridiculed it might be, but the Earl of Warwick's powder continued to be popular. The London Pharmacopoeia of 1721 gave as its ingredients: 2 ounces of scammony (a gum resin that will act as a purgative), 1 ounce of diaphoretic antimony (probably antimony oxide*), and 1 ounce of cream of tartar (potassium hydrogen tartrate). This recipe would make more than a thousand doses of the powder.
Johann Glauber (1604-70) did not reveal how he made a new antimony preparation that he called kermes mineral, and which he invented in about 1651. It, too, was reputed to cure all kinds of illnesses and became particularly popular in France where it was known as poudre de Chartres and used to treat not only fevers, but also more serious conditions like smallpox, dropsy, and syphilis. Glauber kept the process a secret during his lifetime, but it passed to a Dr de Chastenay when he died, and he in his turn confided it to a surgeon, known as La Ligerie, who in his turn entrusted it to a monk, Brother Simon, who used it to treat fellow monks with great success. La Ligerie eventually sold the formula for kermes mineral to King Louis XIV for an undisclosed but considerable sum. The great chemist Berzelius
* Antimony has a common oxide, antimony trioxide (Sb2O3), and a rarer antimony tetroxide (Sb2O4), which can be formed when the ordinary oxide is heated strongly in air.
analysed it many years later and deduced that it was about 40% antimony oxide and 60% antimony sulphide, with small amounts of sodium sulphide depending on its method of preparation. It was still to be found in the US Pharmacopoeia as late as 1910.
Glauber made his kermes mineral from the black ore stibnite. This was boiled with potash (potassium carbonate) to produce a red material, which he assumed to be a new substance, although we know that it was simply another form of antimony sulphide. It was not until a hundred years later that a chemist called Rose was to show that this chemical could exist in two forms with distinctive black and red colours. When it was precipitated from solution it was red, but would revert to the black form on heating. Glauber had found a way to convert stibnite to the red form, although in the process of doing so he had oxidized some of it.
Eventually these various medicines were eclipsed by a much better, and safer, medicament: James's Powder. This was patented in 1747 by Dr Robert James (1705-76), a medic and lifelong friend of Dr Samuel Johnson, who produced the first dictionary of the English language in 1755. James's Powder was also known as Fever Powder, given to produce copious sweating, and was to be part of the medical pharmacopoeia for 150 years. A dose of the Powder would deliver 5-10 mg of antimony and this would have the desired effect. James's Powder was even prescribed for King George III. Samples of it were also recovered from the medical kit of a lost expedition to the Arctic, which set out in the early 1800s, a few of whose abandoned belongings were eventually discovered.
According to the patent, the Powder was made by heating antimony metal to form the oxide and then treating this with animal oil, salt, and molten nitre (potassium nitrate). To safeguard his secret formula, James had in fact submitted a false patent specification. Chemical analysis later showed that his compound was a mixture of antimony oxide and calcium phosphate, and while the former may have been produced as the patent said, the latter was almost certainly added as calcined (burnt) bone, this being the only source of phosphate in the 1700s. An officially approved substitute, which appeared in pharmacopoeias, consisted of antimony sulphide or oxide and powdered hartshorn, but there were many who considered that this was a poor alternative to Dr James's original formulation and his powder continued to be manufactured in London well into the 1800s. The only active ingredient in James's Powder was the antimony but there had to be only a little of it to produce the desired effect - hence the need to dilute it with some inert material like calcium phosphate.
The antimony drug that outlasted all these various proprietary medicines was tartar emetic (potassium antimony tartrate), which was first described in 1631 by Adrian Mynsicht, physician to the Duke of Mecklenburg, although it may well have been used for many years under various guises before this. Glauber published a method of making it in 1648, and his recipe involved boiling three parts of argentine flowers of antimony (a form of antimony oxide) with four parts of cream of tartar (potassium hydrogen tartrate) for one hour, then filtering the solution and evaporating off most of the water; crystals of antimony potassium tartrate would grow when the solution cooled.
The efficacy of this drug was reaffirmed in the mid-1700s by two noted English medics: John Fothergill (1712-80), a Yorkshireman, who became a rich and successful London practitioner, and John Huxham (1692-1768), who was a Fellow of the Royal Society. Huxham came from Devon and he won the prestigious Copley Medal of the Royal Society for his essay on antimony in 1755. In his treatise, he particularly recommended Antimony Wine which was obtained by infusing an ounce of the antimony oxide sulphide in 24 ounces of Madeira wine for 10-12 days. The resulting solution was recommended as an alterant (general tonic), attenuant (slimming aid), and diaphoretic (sweating agent), depending on the dose.
Other patent remedies containing antimony potassium tartrate were available under a variety of names, such as Dr J. Johnson's pills, Hind's sweating ball (used by vets), Mitchell's pills, and there were yet more products given French and German names, either because they came from there or because of the known efficacy of antimonals from those countries.
Antimony sodium tartrate was preferred to the potassium salt because the latter tended to effloresce in dry air, in other words it lost its water component, and if it became completely dry then it was more difficult to dissolve it. The sodium salt did not suffer in this way and it also had another advantage in that it was less of an irritant to the gut. It never succeeded in ousting the potassium salt, because this was easy to manufacture from readily available ingredients and which crystallized well from solution. Tartar emetic came to be regarded almost as a cure-all, but was seen as particularly good for treating fevers. Nevertheless its use declined in favour of arsenical drugs, such as Dr Fowler's Solution (see Chapter 5), and when aspirin became widely available in the 1890s, it became the drug of choice for reducing the high temperatures associated with fevers.
Generally the older antimony remedies fell out of favour in the late 1800s, no doubt due in part to the publicity surrounding the murders that were committed with it. Nevertheless, there was a revival of medical interest in antimony salts in the 1900s after it was discovered, in 1915, to be effective against parasitic infections such as schistosomiasis and trichinosis. Antimony potassium tartrate solution was given by injection in doses that would kill these organisms yet not poison the host body. Treatment with antimony potassium tartrate was generally successful, although patients often experienced the side effects normally associated with antimony poisoning. Occasionally some patients died because of their sensitivity to antimony and there is even a case on record of one patient dying within minutes of being given his first injection.
Drug research into safer antiparasitic antimony compounds came up with antimony sodium bis(pyrocatechol-2,4-disulphonate), which was given the generic name stibophen and marketed under various names such as Fouadin and Trimon. This drug, injected in 100 mg doses, was found to be effective against schistosomiasis, trichinosis, and trypanosomiasis. Side effects were much less likely than with antimony potassium tartrate and only 1 of 2041 people treated with the drug died as a result of antimony poisoning. Another commonly used drug was anthiolimine (antimony lithium thiomalate), which was injected in doses of 1 ml at intervals of 2-3 days, each injection delivering 10 mg of antimony. Slowly the dosage was increased to 4 ml, the object being eventually to administer between 40-60 mg of antimony at a time, the amount depending on the bodyweight of the patient.
Schistosomiasis, which is also known as bilharziasis, is the disease caused by small flat flukes of Schistosoma that infect the veins of various organs of the body. Some colonize the bladder while others colonize the bowel, lungs, or liver. Humans become infected by coming in contact with the larvae of the parasite and these are released from the intermediate hosts that they infect, namely aquatic or amphibious snails. One successful treatment was to inject stibophen, in which antimony is in its lower oxidation state, that is, antimony(III). Today the disease is treated with the drug praziquantel; which does not contain antimony and requires only a single dose to be effective.
Drugs containing antimony in its higher oxidation state, antimony(V), are given to treat another parasitic infection, leishmaniasis, in which the protozoa Leishmania invades the skin forming pimples that grow large and suppurate. Two million cases of this infection are reported every year, mainly of children, and indeed in some countries it is seen as a childhood disease. Antimony-based drugs are used to treat cases of particularly resistant infections, and to check the deadly form of leishmaniasis in which the liver, spleen, and lymph nodes are invaded, and swell alarmingly. Sand flies spread the disease and they often live in houses. These insects also infect animals and wildlife, making them reservoirs of the parasites, thereby making it impossible to break the cycle of human infection by pest control alone.
Antimony compounds in oxidation state III were originally used to treat patients with leishmaniasis but in the 1950s the preference was to use compounds in which the element was in oxidation state V, such as antimony sodium gluconate (pentostam) or meglumine antimonite (glucantim). However, the disease appears to be becoming resistant to these antimony treatments and the reason lies with the oxidation states. In the parasite cells, antimony(V) is reduced to antimony(III) and it is this form which kills them, but some Leishmania cannot reduce antimony(V) to antimony(III) and they thereby protect themselves.
As these uses show, conventional medicine still has need of antimony and, indeed, Professor Nina Ulrich of the University of Hanover, Germany, has recently forecast that its application is likely to increase in the years ahead. If this really does happen then the antimony will also have to be carefully monitored, because its effects really can be unpredictable. Antimosan, the potassium salt of stibophen, was introduced for the treatment of multiple sclerosis, but was not effective. In 1926, a 24-year-old woman suffering from multiple sclerosis was given a series of antimosan injections, and after 17 of these, spread over a period of two months, she appeared to be improving. But with the 18th injection she reacted badly, started vomiting and coughing up blood, then went into a coma from which she never recovered. Some antimony treatments will always be perfectly safe, however. It is still widely used in homoeopathic medicines but such is the dilution of the antimony solution that these are perfectly safe because almost no atoms of the element enter the patient's body.
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