Organic Derivatives of Arsenic

ORGANIC DERIVATIVES OF ARSENIC Aliphatic Compounds.—The first organometallic material, a fuming liquid, was discovered by L. C. Cadet de Gassicourt in 1760 on heating together white arsenic and potassium acetate. The product was subsequently shown by R. W. Bunsen (1837-43) to consist principally of the substance for which the name cacodyl oxide was proposed by J. Berzelius. The inflamma bility of the liquid was due to the presence of a small amount of cacodyl itself Many cacodyl derivatives were described by Bunsen, who also oxidized the oxide to caco dylic acid a colourless crystalline solid readily soluble in water or alcohol. Although cacodyl compounds are very toxic, cacodylic acid is comparatively innocuous and its salts are employed medicinally. Sodium cacodylate has been given both by the mouth and intravenously in tuberculosis, diabetes, leprosy, psoriasis and syphilis. Another arsenical salt, sodium methyl ar sinate, (Arrhenal, new cacodyl), prepared by warming an alkaline solution of sodium arsenite with methyl iodide and alcohol, has been employed in the treatment of the foregoing diseases.

Aromatic Compounds.

Greater success has attended the in troduction of aromatic derivatives of arsenic. By heating aniline arsenate at 18o° Bechamp in 1863 first obtained a substance of acidic character, the sodium salt of which was long afterwards shown by P. Ehrlich and A. Bertheim (19o7) to be sodium p-arsanilate or p-aminophenyl-arsinate (I.).

When introduced into medicine, sodium p-arsanilate was found to be forty times less toxic than sodium arsenite (Fowler's solution) and hence received the name "atoxyl." It became extensively em ployed in the treatment of diseases of protozoal origin such as syphilis and trypanosomiasis. Continued use of the drug was, how ever, sometimes attended by unpleasant secondary effects, e.g., disturbance of vision followed by atrophy of the optic nerve, and accordingly Ehrlich instituted a search for an organic arsenical in which the ratio between curative dose and lethal dose would be as small as possible. This search culminated in the discovery of salvarsan (3 :3' - diamino - 4 :4' - dihydroxyarsenobenzene dihydro chloride) which is sometimes referred to as "6o6" in allusion to the circumstance that Ehrlich and his collaborators examined 605 other substances before they obtained the optimum result with salvarsan. The hydrochloride has several other synonyms, arseno benzol, kharsivan, arsenobillon. Before being administered in travenously, the aqueous solution of the hydrochloride is very carefully neutralized with sodium hydroxide so that the actual drug is the base indicated in formula (II.) . Since the preparation of the perfectly neutral solution of salvarsan base suitable for in travenous injection is a process requiring considerable care, an other drug was introduced under the name of neosalvarsan (syno nyms : neokharsivan, novarsenobenzol, which dis solved to a neutral solution without chemical treatment. This substance (III.) is produced by condensing salvarsan dihydro chloride with sodium-formaldehyde-sulphoxylate, whereby a methyl sulphinate group becomes attached to one of the basic groups of salvarsan.

This neutral sodium salt is more popular than salvarsan because of its ease of administration. The German Pharmocopoeia (1926) describes five modifications of salvarsan. In England salvarsan and neosalvarsan come within the scope of the Therapeutic Sub stances Act (1925). Standard preparations are kept in the Na tional Institute of Medical Research at Hampstead, and biological tests and stability tests are applied to commercial samples. Sal varsan and neosalvarsan are remarkable antisyphilitic remedies and are very widely used for this purpose. Variants have been suggested, such as combinations of salvarsan with silver. French practice has favoured the use of galyl (IV.), a phosphoric acid de rivative of salvarsan, and of luargol, a complex co-ordination com pound of salvarsan containing silver bromide and an antimonyl group It will be noticed that salvarsan and its allies are organic sub stances containing tervalent arsenic, and until recently substances with arsenic in the lower state of oxidation have been most fa voured in therapeutics, but medical opinion is veering round in favour of compounds containing quinquevalent arsenic of which atoxyl was the forerunner. Tryparsamide (V.) or sodium N phenylglycinamide-p-arsinate, has had considerable vogue in the treatment of sleeping sickness, having only 1 o the toxicity of salvarsan.

Stovarsol (Sodium acetylaminohydroxyphenylarsinate, VI.) has been used extensively in the treatment of amoebic dysentery both alone and in conjunction with auramine, emetine and iodine, the complex drug being termed auremetine. These medicaments have been used in yaws, and in early treatment of syphilis.

A diethylamine salt of stovarsol known as acetylarsan has been used for injections, and a precipitation compound with bismuth has been employed in syphilis and yaws.

Toxicology and Forensic Medicine.

The commonest source of arsenical poisoning is arsenious oxide or white arsenic, which in one form is white and opaque like flour, for which it has been mis taken with fatal results. Moreover, as it has little taste and no colour it is easily mixed with food for homicidal purposes. When combined with potash or soda it is used to saturate flypapers, and strong solutions can be obtained by soaking these in water; this fact has also been used with criminal intent. Copper arsenite (or Scheele's green) used to be much employed as a pigment for wall-papers and fabrics, and toxic effects have resulted from their use. Metallic arsenic is probably not poisonous, but as it usually becomes oxidized in the alimentary canal the symptoms of arseni cal' poisoning follow its ingestion.

In

acute poisoning the interval between the reception of the poison and the onset of symptoms ranges from ten minutes or even less, if a strong solution be taken on an empty stomach, to twelve or more hours if the drug be taken in solid form and the stomach be full of food. The usual period, however, is from half an hour to an hour. In a typical case a sensation of heat develop ing into a burning pain is felt in the throat and stomach. This is soon followed by uncontrollable vomiting and later by severe purging, the stools being first of all faecal but later assuming a rice-water appearance, and often containing blood. The patient suffers from intense thirst, which cannot be relieved, as drinking is immediately followed by rejection of the swallowed fluid. There is profound collapse, the features are sunken, the skin moist and cyanosed. The pulse is feeble and irregular, and respiration is difficult. The pain in the stomach is persistent, and cramps in the calves of the legs add to the torture. Death may be preceded by coma, but consciousness is often maintained to the end. The simi larity of the symptoms to those of cholera is very marked, but if suspicion arises it can be cleared up by examining any of the se cretions for arsenic. More rarely the poison attacks the nerve centres, and gastrointestinal symptoms may be almost or quite absent. In such cases the acute collapse occurs in company with both superficial and deep anaesthesia of the limbs, and is soon followed by coma terminating in death. In criminal poisoning re peated doses are usually given, so that such cases may not be typical, but will present some of the aspects of acute and some of chronic arsenical poisoning. As regards treatment, the stomach should be washed out with warm water by means of a soft rubber tube, an emetic being also administered. Then, if available, freshly precipitated ferric hydrate should be given, which can be prepared by adding a solution of ammonia to one of iron per chloride. The precipitate is strained off, so that the patient may swallow it suspended in water. While this is being obtained, mag nesia, castor oil or olive oil can be given ; or failing all these, copious draughts of water. The collapse should be treated with hot blankets and bottles, but medical aid should be summoned for the administration of subcutaneous injections of brandy, ether or strychnine, and for injections of morphia to lessen the pain.

Arsenic may be gradually absorbed into the system in very small quantities over a prolonged period, the symptoms of chronic poisoning resulting. The commonest sources used to be wall papers, fabrics, artificial flowers and toys : also certain trades, as in the manufacture of arsenical sheep-dipping. But cases arising from these causes now occur very rarely. The earliest symptoms are slight gastric disorders, loss of appetite and general malaise, followed later by collicky pains, irritation of eyelids and skin eruptions. But sooner or later peripheral neuritis develops, usu ally beginning with sensory disturbances, tingling, numbness, for mication, and usually cutaneous anaesthesia. Later the affected muscles become exquisitely tender, and then atrophy, while the knee-jerk or other reflex is lost. Pigmentation of the skin may occur in the later stages. Recovery is very slow, and in fatal cases death usually results from heart failure.

After acute poisoning, the stomach at a post-mortem presents signs of intense inflammation, submucous haemorrhages are usu ally present, but perforation is rare. The rest of the alimentary canal exhibits inflammatory changes in a somewhat lesser degree. After chronic poisoning a widely spread fatty degeneration is present. Arsenic is found in almost every part of the body, but is retained in largest amount by the liver, secondly by the kidneys. After death from chronic poisoning it is found present even in the brain and spongy bone. The detection of arsenic in criminal cases is effected either by Reinsch's test or by Marsh's test, the urine being the secretion analysed when available.

Production and Exploitation of Arsenic.

In 1926 the production of arsenic in the United States, Canada and Mexico was about 16,000 tons, whereas the output from the Old World, including Belgium, England, France, Germany, Greece and Japan, was about I1,000 to 12,000 tons. These data are somewhat less than the estimates of the previous year (1925). The United States maintains its lead in both the production and consumption of arsenical compounds. Among the latter are the well-known in secticides, calcium arsenate and lead arsenate, which are employed extensively. Arsenical compounds are also employed as wood pre servatives or as clearing agents in glass manufacture.

BIBLIOGRAPHY.-G.

A. Roush and A. Butts, The Mineral Industry, Bibliography.-G. A. Roush and A. Butts, The Mineral Industry, Its Statistics, Technology and Trade (New York, 1927) ; W. H. Martindale and W. W. Westcott, The Extra Pharmocopoeia, (1Ith Edition, 1925), and Salvarsan (191I) ; E. Fourneau, Organic Medica ments and their Preparation (1925) ; G. T. Morgan, Organic Com pounds of Arsenic and Antimony (1918) . (G. T. M.)