  Duhamel and Rebiere(6)(7) showed that an injection of a trace of red colloidal selenium into rabbits increased urea excretion regularly. In other cases satisfactory results were claimed and the liver showed some lesions. The histological modifications produced by injections into rabbits are most apparent in the liver and kidneys. In the distribution of colloidal preparations in the animal body by injection, Duhamel and Juillard(8) found that the liver contained the greatest amount. Six years later the former(9) used a similar preparation introduced into the animal intravenously, and selenium was again found in the liver, although in smaller quantity. Sulphur compounds have similar physiological action. It is known that triphenylstibine sulphide, or sulphoform, (C6H5)3SbS, has a curative effect in skin diseases, as it liberates “nascent” sulphur on the skin. It is equally natural to expect some organic selenium compound which liberates finely divided selenium to exert a remedial influence on animal bodies. The selenoquinazolone prepared in the course of this research and described more fully in another section of the paper, has this prospect. The quinazolone has the following structure: Experiments were carried on at L’Institut Pasteur in Paris under the supervision of M. Borel for the treatment of cancer in mice. No human subjects were experimented upon, although results were claimed by using selenides and their oxidized salts. Selenium dyes were found to be medicinals, although no relation has yet been established between constitution of these organic dyes and their therapeutic value. Wassermann(10) made several eosin preparations, by coupling the sodium derivative with potassium selenocyanide. The red dyestuff thus prepared is stated to be easily soluble in water. Wassermann, Keysser and Wassermann(11) made experiments with it, chemotherapeutically, on animal tumors. When the solution was injected The following is the structure of 2-selenocyanideanthraquinone— which has also been reported to have medicinal uses(13). P. Ehrlich and Hugo Bauer(14) synthesized from p.p'-diamino-diphenyl-methane the red dye 3,6-diaminoselenopyronine. The dye has been used upon mice and caused pronounced edema. The toxicity of both the selenopyronine and the corresponding sulphur compound was compared under similar conditions in the same experiment, and it was found that the selenium dye was toxic in 1/3000 gram, but the sulphur dye was toxic in 1/2500 gram per twenty gram weight of the animal. This physiological activity was noted years ago with the inorganic compounds of selenium and Berzelius(15) described the poisonous effect of hydrogen selenide quite impressively; “In order to get acquainted with the smell of this gas I allowed a bubble not larger than a pea to pass into my nostril; in consequence of its smell I so completely lost my sense of smell for several hours that I could not distinguish the odor of strong ammonia even when held under my nose. My sense of smell returned after five or six hours, but severe irritation of the mucous membrane set in and persisted for a fortnight.” The writer has been working on the gas for some time and was also quite seriously affected once, the injury persisting for many Bruere(16) showed that when hydrogen sulphide was passed into blood solution sulphemoglobin was produced in considerable quantity, due to the chemical action of sulphur and hematin. He stated further that sulphemoglobin may be found in animal blood when a large amount of the gas has been inhaled. He made selenhemoglobin in the same manner. Sixteen years later, Clarke and Hurtley also proved that selenhemoglobin may be made by passing hydrogen selenide into blood(17). These experiments may be interpreted to mean that the oxy-hemoglobin is transformed into an organic complex of sulphur or selenium, and that the transference may be more rapid and powerful in the case of hydrogen selenide. Biological investigations have sufficiently proved that dyestuffs of the phenazine, oxazine, thiazine, acridine series show an injurious effect on protozoa, especially those dyes containing substituted amino groupings and of a simple structure(18). In the case of the thiazine dyes of the methylene blue class, the physiological importance has well recognized in their use as feeble antiseptics and analgesics. Ehrlich and Guttmann(19) initiated the use of methylene blue as an antiperiodic and its use in that line has been continued. In the field of the selenazine dyes, pharmacologists have not yet paid much attention to them, on account of the newness of the discovery, but P. Karrer claims that they are indisputably “vital dyestuffs”(20). The prospect of synthesizing selenazine dyes and their use as drugs seems to be bright, judging from the fact that they are easily prepared and capable of many combinations, especially of the ease with which they form organic complexes with arsenic compounds. Formula (I) is known, as 1, 3-dinitrobenzoselenazine(21), which was obtained by the action of picryl chloride on the zinc salt of o-aminoselenophenol; the product (picrylaminoselenophenol) being then treated with alkali and thus converted to the dye, which upon experimentation showed marked effects upon protozoa and bacteria. Formula (II), known as 3-(p-phenylarsonic)-aminoselenazine, is red in dilute alkali and green in mineral acid, and is a typical dye in a series from the coupling of selenodiphenylamine with arsenic compounds. All possess similar toxicity as the thiazine dyes(20). Other selenazines are listed in the bibliography(22). No less than half dozen thioureas are commonly used as drugs. Thiourea itself paralyzes the nerve centers, and is employed commercially for photograph fixing and for removing stains from negatives; thiuret, C6H7N3S2, serves as a substitute for iodoform; thiosinamine-ethyliodide, or tiodine, IH5C2H2NCSNHC3H5, is used for relief of lesions of the central nervous system; allylthiourea or thiosinamine, (NH2)SC.NHCH2CH:CH2, for aiding the absorption of connective tissues, for treatment of burns, keloids, urethral diseases, sclerotic conditions of the ear(23). Selenocarbamide and a number of its derivatives have been prepared and studied. One class of seleno ureas has been patented as pharmaceutical products by Chem. Fabrik von Heyden(24), and are prepared by the action of hydrogen selenide on alkylcyanamides, RNH.CHN + H2Se = RNH.CSe.NH2 They possess pronounced therapeutic value and, serve as intermediate products in the production of more stable alkyl halide additive compounds. Other carbamides ranging from seleno urea itself(25), (III) and a cyclic urea(26) (IV) are described in the literature: The latter, known as ethylene-selenourea, may be classified also in the azole group as 2-iminotetrahydroselenazole (V). The literature for the other normal carbamides is listed in the bibliography(27). Selenoantipyrines, selenosaccharine, selenoindigoes have also been prepared. Thiophene and its derivatives are of considerable therapeutic interest. Thiophene itself is found to be useful in lessening the elimination of sulphuric acid in urine, and is employed in the dermatological practice. Sodium thiophene sulphonate, thiophenetetra-bromide, thiophene diiodide, are all medicinals(23). A number of selenophenes are recorded in the literature. Their relation to the selenazoles may be easily seen from the following formulas: Selenophene Selenazole Dimethyl selenophene was prepared from acetonyl acetone and phosphorous pentaselenide, The compound thus obtained is stated to have the same odor as thiophene, but no mention is made in regard to its uses(28). Selenophene was prepared from sodium succinate and phosphorous triselenide, or by conducting ethylselenide through hot tubes(29). Some selenazoles find application also in medicine. At present only the isoazoles are known to have physiological uses. One of them was prepared from anthraquinone selenocyanide, by the action of ammonia under pressure(30). Another type of azoles, benzoselendiazole (piaselenol) and five of its derivatives, have been also described as medicinals(31). The diazole itself has the following structure, or Diazoles of the following structure are also known, but no data were found, regarding their physiological action(32): Dimethyl-seleno-diazole Diphenyl-seleno-diazole Sulphides and disulphides have curative power. Dimethylsulphide is used for internal treatment, di-o-aminophenyldisulphide is used for intramuscular injections. Diallyl sulphide is also a medicament. Methyl selenide has some effect on the internal parts of the body(33). Hanzlik and Tarr(34) at the American University Experimental Station, showed that a number of selenium compounds act as skin irritants: e.g., dichlorodiethyl selenide, dichlorovinyl selenide, trichlorodiethyl selenide and selenium mustard oil. The first mentioned proved as potent as the sulphide, but the others fell somewhat below in their effects. Diantipyryl selenide is another therapeutical agent(35). The diselenides occupy an important place of their own. The selenophenols do not remain unchanged in the air, but are always oxidized to the diselenides, which can be again reduced to the selenophenols. So far only the diselenides of anthraquinone and their phenols are recognized remedies(36). |
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