The arsenicals (compounds which contain the heavy metal element arsenic, As) have a long history of use in man – with both benevolent and malevolent intent. The name ‘arsenic’ is derived from the Greek word ‘arsenikon’ which means ‘potent'”. As early as 2000 BC, arsenic trioxide, obtained from smelting copper, was used as a drug and as a poison. Hippocrates (460 to 377 BC) used orpiment (As2S3) and realgar (As2S2) as escharotics. Aristotle (384 to 322 BC) and Pliny the Elder (23 to 79 AD) also wrote about the medicinal properties of the arsenicals.
Galen (130 to 200 AD) recommended a paste of arsenic sulphide for the treatment of ulcers. Paracelsus (1493 to 1541) used elemental arsenic extensively. He is quoted as saying ‘All substances are poisons … The right dose differentiates a poison and a remedy’ – an apt statement for the arsenicals.
In the eighteenth century, Fowler’s solution (1% potassium arsenite) was used for the relief of various ailments and remained very popular for over 150 years.
In the nineteenth century arsenicals were ingested, inhaled as vapours, injected intramuscularly and intravenously, and given in enemas. They caused
cutaneous capillary dilatation – the fashionable ‘milk and roses’ complexion. Arsenicals were used to treat acne caused by iodides and bromides, and were later added to bromide containing mixtures to prevent bromide eruptions.
By the early 1900s, physicians were using arsenicals to treat pellagra and malaria. In 1912 arsenic was recognized as the best agent in the Pharmacopoeia’. At about the same time Ehrlich’s experiments yielded arsphenamine, and arsenicals remained the mainstay of treatment for syphilis for nearly 40 years until the advent of penicillin.
Arsenicals were also popular in treating vaginal discharge of any origin. They were supplied as vaginal inserts or powder for insufflation, and were apparently effective against trichomonas. However, they were superseded by metronidazole – the first clinical reports of its efficacy appearing in 1959.
Today arsenicals are still used in the treatment of sleeping sickness. Some Indian women take arsenic containing medicines during the first trimester of pregnancy, believing that this increases their chance of having a son.
In humans no nutritional role is known for arsenic, although it has a function in animal husbandry – organic arsenicals are added to animal feed to control disease and promote growth. However, small doses of inorganic arsenicals have long been felt to have a ‘tonic’ or ‘alternative’ property. Large quantities of arsenical ores were consumed by the ‘arsenic eaters’ of the Austrian mountains in the belief that they improved their stamina, appearance and sense of wellbeing. This may be just folklore, but it has been suggested that arsenic may be an unrecognized essential nutrient, in which Western diets are deficient’.
Arsenic (atomic number 33, atomic weight 75) is a member of the nitrogen group in the periodic table. It is classified as a transitional element or metalloid. Arsenic can exist in three different valency states: elemental arsenic (zero oxidation state); trivalent; or pentavalent arsenic. It forms alloys with metals and also readily reacts with carbon, oxygen and hydrogen, forming covalent bonds. The chemistry of arsenic is further mystified by the practice of often not specifying in published work the chemical nature of the arsenic-containing compound, but just referring to it as ‘arsenic’.
The toxicity of an arsenical varies with the valency state (trivalent are more toxic than pentavalent compounds), the physical state of the compound, and the rates of absorption and elimination. Elemental arsenic (the metalloid) is non-toxic even if eaten in substantial amounts. Of the inorganic compounds, those containing pentavalent arsenic (derivatives of arsenic acid, H3AsO4, the arsenates) are much less toxic than those containing trivalent arsenic. Inorganic compounds of trivalent arsenic are derivatives of arsenious acid, H2As203 (the arsenites) and include arsenic trioxide (As203, ‘the poison of poisons’). Arsine (AsH3, a gaseous hydride of arsenic trioxide) is the most toxic of all the arsenicals. Its toxic effects are distinct
because it is inhaled, rather than absorbed through the skin or gastrointestinal tract.
Organic arsenicals contain arsenic (either trivalent or pentavalent) linked to a carbon atom by a covalent bond. In general, they are excreted more rapidly than inorganic compounds. The most important trivalent organic arsenicals are the arsphenamines, which were used in the treatment of syphilis. Pentavalent organic compounds were used in the treatment of sleeping sickness.
This inorganic compound of trivalent arsenic has been used extensively as a remedy and as a poison. In 1786 Thomas Fowler, an English physician, reported the use of a flavoured solution of arsenic trioxide in the cure of agues, remittent fevers, and periodic headaches. Fowler, with Hughes (an apothecary) had identified arsenic as the major constituent of the ‘ague drops’ patented by Thomas Wilson, a London chemist, in 1781.
Fowler’s solution (1% potassium arsenite, K AsO2) was used as a tonic for anaemia and rheumatism. It was used to treat psoriasis, eczematous eruptions, dermatitis herpetiformis, asthma, cholera and syphilis. In 1865, Fowler’s solution was the first chemotherapeutic agent used in the treatment of leukaemia (which was first described in 1845). It was chosen as it was known to produce smoother coats and improve digestion in horses! In human leukaemics it produced a transient improvement. In 1931 Forkner and Scott, at Boston City Hospital, ‘rediscovered’ Fowler’s solution for the treatment of chronic myeloid leukaemia, and arsenicals and irradiation remained the treatment of choice until busulphan was introduced in 19537.
Arsenic trioxide has an even longer history of use with malevolent intent. Its popularity as a poison was probably due to its availability, inexpensiveness, and lack of taste and odour. It has the appearance of sugar (it is also known as ‘white arsenic’) and does not destroy the appetite. It is the most toxic arsenical after arsine, but does not produce instantaneous death. In Arsenic and old lace, John Kesselring’s 1941 play, half a teaspoonful of strychnine and a pinch of cyanide were also added to the teaspoonful of ‘arsenic’ in a gallon of elderberry wine; the concoction which the old ladies used rapidly to dispatch their gentlemen callers.
One of the earliest documented cases of homicide caused by an arsenical occurred in 55 AD, when Nero poisoned Britannicus to secure his Roman throne. The Borgias used arsenicals. In the Middle Ages the poisoner became a part of social and political life. White arsenic acquired a reputation, it was called ‘poudre de succession’ or ‘inheritance powder’. It was the favourite poison in nineteenth century France (phosphorus was the second most popular). However, its use rapidly declined towards the end of the century. This coincided with the development of a highly sensitive assay for arsenic. It continues to be used for suicidal purposes.
In the early 1900s physicians began using the less toxic organic arsenicals. About 32 000 organic arsenic-containing compounds have been made – more than any other trace element. Sodium cacodylate and sodium arsanilate were used for the treatment of pellagra, malaria and sleeping sickness.
Breinl and Thomas at the Liverpool School of Tropical Medicine had produced atoxyl (a pentavalent compound) which was used to treat sleeping sickness. However, its high arsenic content produced optic atrophy.
This work inspired Paul Ehrlich. He instructed his workers to study the organic arsenicals to find ‘the silver bullet’ against the syphilis spirochaete (which was first identified in 1905). The therapeutic problem was how to obtain maximum effect on the parasite with minimal effect on the body’s tissues.
In 1907, the 606th preparation of an arsenobenzene compound (containing 32% arsenic) was synthesized. Its potential was overlooked for two years but later work, using syphilitic rabbits, convinced Ehrlich that arsphenamine was ‘the silver bullet’. It was first used to treat human syphilis in 1911. Hoechst eventually gained approval to market Salvarsan (also called ‘healing arsenic’ or ‘606’) and 65 000 free samples were sent to doctors all over the world. Arsphenamine was enthusiastically received by the international scientific periodicals, and was the subject of banner headlines in the newspapers. Ehrlich warned that the drug might be harmful, because of its potency, and urged caution with intravenous administration.
The treatment of syphilis with arsenicals was a lengthy and unpleasant business: ‘two minutes with Venus, 2 years with mercury’ (aphorism, J Earle
Moore). Arsphenamine was given by intravenous infusion, each treatment lasting an hour. Courses of arsenical treatments would be alternated with mercury rubs (which stained the patient’s underclothes and had a characteristic odour) or intramuscular mercuric succinamide. Later, 6-8 week courses of intravenous arsenical were alternated with 6-8 weeks of intramuscular bismuth. The minimum duration of treatment exceeded 18 months; 20 injections of arsphenamine and 30 to 40 injections of bismuth.
The development of neoarsphenamine (Neosalvarsan or ‘909’), a less toxic derivative of arsphenamine which could be injected intravenously, enabled more rapid treatments, but was still associated with nausea and vomiting. Oxophenarsine hydrochloride (Mapharsen) could be injected rapidly and produced fewer reactions. In children sulpharsphenamine was given intramuscularly. It also produced nausea and vomiting, and occasionally a ‘nitratoid reaction’ – sweating, diarrhoea, hypotension and collapse.
Silver arsphenamine was used for the treatment of central nervous system syphilis – a small amount being introduced into the cerebrospinal fluid via lumbar puncture. This was a very painful treatment which, in rare cases, caused serious spinal cord damage. Benefit may have resulted from the production of an aseptic meningitis or by altering the permeability of the blood brain barrier to intravenously administered drugs. In patients treated early, and those conscientious enough to complete the full course of treatment, arsenicals produced at least as good a cure rate as modern day syphilis therapy’0. They were used widely in Europe until the late 1940s and even later in the Far East, where they were also used to treat yaws.
Penicillin was first advocated as a treatment for syphilis in 1943 but was not generally available for several years. It had the great advantage that it could be given over a short period of time when the patient was most apprehensive and anxious for a cure.
Today arsenicals are still used in man, in the treatment of African trypanosomiasis. This causes sleeping sickness which is always fatal without treatment. The original arsenical used was tryparsamide (containing 25% pentavalent arsenic in organic combination). This was associated with a high incidence of toxic reactions and could cause blindness. As the parasites’ resistance to it was increasing, it has been replaced by two other organic arsenicals – melarsoprol (Mel B), containing 18.8% trivalent arsenic, and melarsonyl (Mel-W). Both are given by intravenous injection and are toxic drugs. They may cause a potentially life threatening reactive arsenical encephalopathy.
Reprint from Journal of the Royal Society of Medicine Volume 86 May 1993 Pg. 287Home
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