Santonin

Santonin is a drug which was widely used in the past as an anthelminthic, a drug which expels parasitic worms (helminths) by paralyzing them, allowing them to be passed out of the body. Santonin was formerly listed in U.S. and British pharmacopoeia, but it has fallen out of use with the development of safer ascaricides and is no longer registered as a drug in most countries....These effects usually pass off in a few days. Large doses, however, produce toxic effects, aphasia, muscular tremors and epileptiform convulsions, and the disturbances of vision may go on to total blindness.Santonin is an active agent, and, in improper doses, is capable of producing serious symptoms, and even death. As small a dose as 2 grains is said to have killed a weakly child of 5 years, and 5 grains produced death in about 1/2 hour in a child of the same age. Among the toxic effects may be mentioned gastric pain, pallor and coldness of the surface, followed by heat and injection of the head, tremors, dizziness, pupillary dilatation, twitching of the eyes, stertor, copious sweating, hematuria, convulsive movements, tetanic cramps stupor, and insensibility. Occasionally symptoms resembling cholera morbus have been produced, and in all cases the urine presents a characteristic yellowish or greenish-yellow hue. We have observed convulsions caused by the administration of 'worm lozenges.' Death from santonin is due to respiratory paralysis, and post-mortem examination revealed in one instance a contracted and empty right ventricle, and about an ounce of liquid, black blood in the left heart, an inflamed duodenum, and inflamed patches in the stomach (Kilner).. . .Santonin often produces a singular effect upon the vision, causing surrounding objects to appear discolored, as if they were yellow or green, and occasionally blue or red; it also imparts a yellow or green color to the urine, and a reddish-purple color if that fluid be alkaline. Prof. Giovanni was led to believe that the apparent yellow color of objects observed by the eye, when under the influence of santonin, did not depend upon an elective action on the optic nerves, but rather to the yellow color which the drug itself takes when exposed to the air. Santonin colored by the air does not produce this effect, which only follows the white article. The air gives the yellow color to santonin, to passed urine containing it, and to the serum of the blood when drawn from a vein, and, according to Giovanni, it is owing to its direct action upon the aqueous humor, where it is carried by absorption, that objects present this color. The view now held, however, is that of Rose, that the alkaline serum dissolves the santonin, which then acts upon the perspective centers of the brain, producing the chromatopsia or xanthopsia. Santonin is a drug which was widely used in the past as an anthelminthic, a drug which expels parasitic worms (helminths) by paralyzing them, allowing them to be passed out of the body. Santonin was formerly listed in U.S. and British pharmacopoeia, but it has fallen out of use with the development of safer ascaricides and is no longer registered as a drug in most countries. Santonin has the effect of paralyzing the anterior (front) end of the worm, while having a stimulant effect on the anterior end, depending on the concentration. Because of this, the worm cannot coordinate itself, and loses its ability to maintain its position in the host. By using a purgative, the worm can easy be passed out. Experiments in the 1880s showed that even after 40 hours, santonin had no lethal effect on roundworms using a saturated solution in dilute alkali. Santonin can be converted to santonic acid (C15H20O4) via based-catalyzed hydrolysis followed by a multistep rearrangement process. Santonin dissolves in alkalies with formation of salts of this carboxylic acid. Santonin, in acetic acid solution, when exposed to sunlight for about a month, is converted into (colorless) photosantonic acid (C15H22O5) which is generally regarded as less toxic. The ethyl ester of the latter is obtained when an alcoholic solution of santonin is exposed to sunlight (Sestini). A yellow coloration is developed upon exposure of santonin to light. Santonin is optically levorotatory. Santonin is an organic chemical consisting of colorless flat prisms, turning slightly yellow from the action of light and soluble in alcohol, chloroform and boiling water. It is derived from santonica (the unexpanded flower-heads of Artemisia maritima var. stechmanniana). Others refer to A. cina or A. chamaemelifolia as being the derivative species. According to the US Pharmacopoeia, santonin occurs 'in colorless, shining, flattened, prismatic crystals, odorless and nearly tasteless when first put in the mouth, but afterward developing a bitter taste; not altered by exposure to air, but turning yellow on exposure to light. Nearly insoluble in cold water; soluble in 40 parts of alcohol at 15 °C. (59 °F.), in 250 parts of boiling water, and in 8 parts of boiling alcohol; also soluble in 140 parts of ether, in 4 parts of chloroform, and in solutions of caustic alkalies. When heated to 170 °C. (338 °F.), santonin melts, and forms, if rapidly cooled, an amorphous mass, which instantly crystallizes oil coming in contact with a minute quantity of one of its solvents. At a higher temperature, it sublimes partly unchanged, and, when ignited, it is consumed, leaving no residue. Santonin is neutral to litmus paper moistened with alcohol. Santonin yields, with an alcoholic solution of potassium hydrate, a bright pinkish-red liquid, which gradually becomes colorless. From its solution in caustic alkalies, santonin is completely precipitated by supersaturation with an acid'. The full biosynthesis of α-santonin has not been elucidated but α-santonin bears much similarity to parthenolide. The proposed biosynthesis begins with the cyclization of farnesyl diphosphate (FPP) to (+)-germacrene A by a sesquiterpene synthase. (+)-germacrene A hydroxylase then hydroxylates the isopropenyl side chain. The oxidation of germacratrien-12-ol to germacratrien-12-oic acid via the intermediate germacratrien-12-al is done by NADP+-dependent dehydrogenase(s). Germacratrien-12-oic acid is then hydroxylated at C6 subsequently followed by lactonization forming (+)-costunolide. It was proposed that the methylene of (+)-Costunolide is reduced before the second ring closure. The bicyclic decalin ring system is formed via the eudesmyl cation followed by hydroxylation at C1. Further oxidation at C3 forms the β-ketohydroxyl which upon elimination of H2O completes the proposed biosynthetic pathway of α-santonin. Santonin was developed in the 1830s by German chemists by extracting the chemical from Artemisia cina, a plant from Turkmenistan. At the time Artemisia was often used as an antihelminthic remedy, and as a perennial it was widely accessible. A common remedy wt the time used an infusion of 5-10 g herb in 500ml water. Castor oil could be used to help the expulsion process. It was reported that by 1843 candy lozenges were available in Germany which contained santonin.