Santonin

SANTONIN (Pharmacopoeia VII), the active principle of wormseed, Artemisia Cina Berg., A. maritima L., A. mexicana, and other species, was first discovered in 1830 by the pharmacist Kahler and independently by Alms in the dried, unopened inflorescences (incorrectly called wormseed) of this plant, which grows wild in Kazakhstan, in the Chimkent region. Santonin possesses the properties of ketones and is simultaneously a lactone of santoninic acid, C₁₅H₁₈O₃, to which the following structure is attributed: O-----CO CH₃ /

It is a colorless crystalline powder (rhombic prisms or plates), odorless, with a slightly bitter taste, dissolving in 5,000 parts of cold and 250 parts of boiling water (neutral reaction), in 44 parts of cold and 3 parts of boiling 90% alcohol, in 75 parts of ether, and in 4 parts of chloroform. It also dissolves in fatty and essential oils and alkalis. Under the influence of light, it undergoes a photochemical change, forming a yellow substance, chromosantonin, which reverts to santonin after crystallization. It melts at 170°, subliming. The optical rotation [α]^D = -171.6° for a 2% solution in 90% alcohol. Santonin is produced at the Chimkent Pharmaceutical Plant. Its extraction from wormseed, which contains from 1 to 3.5% santonin, is based on the fact that when treated with slaked lime, it converts into the calcium salt of santoninic acid. Upon adding hydrochloric acid to an aqueous solution of this salt, santonin precipitates, which is purified with ammonia and crystallization from alcohol and decolorized with charcoal. In a 50% solution of sulfuric acid heated to 100°, santonin gives a blood-red coloration with a drop of ferric chloride. When heated with hydrochloric acid, santonin turns into the isomeric desmotroposantonin, obtained synthetically in 1930. In the acidic environment of the stomach, santonin partially dissolves and is absorbed (more strongly on an empty stomach). Further, in the small intestine, it dissolves in the alkaline intestinal juice, converting into the sodium salt of santonin, which is absorbed, exhibiting a general effect. Santonin is primarily a nerve poison. Most often, a distortion in color perception is observed—xanthopsia, which is usually explained by a specific effect on the retina, but this question has not yet been precisely clarified. Apparently, santonin reduces the ability to perceive the most refractive rays of the spectrum. In cases of poisoning with large doses, convulsions are observed; in experimental animals, breathing becomes irregular, slows down, and the animal dies from asphyxia. After the usual doses used in medicine, santonin is excreted almost entirely in a colored form, mainly in the urine, the yellow color of which turns red upon the addition of caustic alkalis. The colored substance was also detected in sweat, and upon the administration of the potassium salt of santonin, also in blood plasma and feces. The principle of santonin's action on ascarids is not yet sufficiently clarified. In vitro, ascarids live for a long time in santonin solutions, which some authors explain by the absence of bile acids, which enhance the effect of santonin in the body. According to Trendelenburg, santonin strongly excites the musculature of worms, causing its strongest contraction, and this phenomenon is specific to santonin and only regarding worms. In recent times, the assumption has been made that santonin is entirely absorbed in the intestine and exhibits its effect only upon its secondary excretion into the intestine, after it has undergone certain changes in the body. That such excretion into the intestine with subsequent manifestation of anthelmintic action takes place is proven by the anti-ascarid efficacy of santonin upon subcutaneous administration of its soluble sodium salt (Morinaka and Ischikawa, 1926; Shultz and Abuladze) or by santonin suppositories (Seishin, 1924). Santonin does not show a noticeable effect on migrating ascarid larvae (Smirnov, 1931). Santonin is most effective against ascarids (various representatives of the family Ascarididae, parasites of humans and other mammals) and pinworms; it acts more weakly on whipworms and is completely ineffective against most other nematodes, cestodes, and trematodes. Practically, santonin finds application in human ascariasis (Ascaris lumbricoides), swine ascariasis (A. suum), and ascariasis in dogs and cats (Toxascaris leonina, Toxocara canis, T. mystax). It is prescribed in the form of powder, lozenges, and in an oil solution with a preliminary diet and emptying of the stomach. A subsequent strong laxative (castor oil, calomel) expels the stunned or dead worms with feces. In recent years, a number of reports have appeared in the foreign press in which the anti-ascarid efficacy of santonin was disputed. Through special studies conducted by the All-Union Institute of Helminthology and the Scientific Research Institute of Pharmaceutical Chemistry, these data have been refuted, and it has been established that when applied properly (necessarily with a laxative) and in correct doses, santonin removes 70-95% of ascarids. Santonin expels not only adult but also young forms of ascarids. The passage of ascarids is noted on the 4th, 5th, and even 6th day after taking santonin (Shikhobalova and Sokolova). The sensitivity of different individuals to santonin varies greatly. With age, tolerance to santonin increases. The results from the use of santonin are not always the same, which should be attributed to a number of incidental factors (quantity and quality of the laxative, conditions and technique of administration, and dosage). Based on a specially conducted study, Shikhobalova and Sokolova come to the following conclusion: precise age-based dosages of santonin (provided a normal physical status) are one of the factors playing a fundamental role in the success of therapy for ascariasis in children. For widespread use, a dose of santonin of 0.015 per day per one year of a child's life and 0.3 for an adult (per day) can be recommended. The daily dose can be given in three doses with an hour interval or in two doses with an interval of 2-3 hours. The maximum dose for a human according to the pharmacopoeia is 0.1 at one time and 0.3 daily, but some allow for larger dosages. The dose for a pig is 0.03-0.05 per 1 kg of live weight, for a dog 0.03 per 1 kg, for a cat 0.1-0.2 per head. With careless use, poisoning can occur. For the clinical picture of poisoning and treatment, see Poisoning. Santonin is stored with caution in a place protected from light in orange glass.

I. Pevinshtein. Detection of santonin in forensic cases. The objects of investigation can be the contents of the stomach and intestines, and vomitus. Detection is successful only a short time after poisoning. The material under investigation is extracted with water alkalized with caustic soda while heating. The solution is extracted with benzene to remove impurities, then acidified with hydrochloric acid and extracted with chloroform. The latter is evaporated, and the following reactions are performed with the residue: 1) a drop of an alcoholic solution of the residue is mixed with 1 drop of a 2% alcoholic solution of furfural and 2 cm³ of concentrated sulfuric acid and heated in a porcelain dish on a water bath: a purple-red coloration appears, turning into blue-violet and blue, yielding a black precipitate after several hours. The reaction occurs with an excess of furfural in relation to santonin.

In the absence of the latter, furfural gives only a pale pink coloration, which quickly turns brown. 2) In sunlight, the residue turns yellow and, upon dissolution in caustic alkalis, takes on a reddish color, which then disappears.