Santonin

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ImageFile1 = Alpha-santonin-from-xtal-3D-balls.pngIUPACName=(3S,3aS,5aS,9bS)-3,5a,9-trimethyl-3a,4,5,9b-tetrahydro-3H-benzo [g] benzofuran-2,8-dione
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CASNo=481-06-1
PubChem=221071
SMILES=CC1C2CCC3(C=CC(=O)C(=C3C2OC1=O)C)C
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Formula=C₁₅H₁₈O₃
MolarMass=246.30162
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Santonin is a drug which was widely used in the past as an anthelminthic, a drug that expels parasitic worms (helminths) from the body, by either killing or stunning them. Santonin was formerly listed in U.S. and British pharmacopoeia but has fallen out of use with the development of safer ascaricides and is no longer registered as a drug in most countries [Modern Drug Encyclopedia and Therapeutic Index, Sixth Edition, Drug Publications Inc, 1955] .

Reactions and properties

Santonin can be converted to santonic acid (C₁₅H₂₀O₄) via based-catalyzed hydrolysis followed by a multistep rearrangement process. [ [http://www.cem.msu.edu/~reusch/VirtualText/rearang2.htm Base-catalyzed rearrangements] ]

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 which is the unexpanded flower-heads of "Artemisia maritima". [Per the "Encyclopedia Britannica" (1911 edition)] [Modern botanicals also list "Artemisia cina" or Levant wormwood as the definitive source; this is also backed up by statements in formularies published in the heyday of santonin use such as "King's American Dispensatory".] [ [http://www.henriettesherbal.com/eclectic/kings/artemisia-pauc_sant.html King's American Dispensatory, 1898] (this work is now in the public domain)] [ [http://www.botanical.com/botanical/mgmh/w/worlav36.html Botanical.com] (article on Levant Wormwood, primary source of santonin)]

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" [original source, US Pharmacopoeia, 1898] .

Historical pharmacological use

As noted above, santonin was formerly used as an anthelminthic, typically administered with a purgative. Santonin was used in treatment of infestation by the roundworm "Ascaris lumbricoides" and in ascarid parasitoses in general (including threadworm parasitosis). It is ineffective in treatment of tapeworm infestation.

The "Encyclopedia Britannica" (1911) notes that the typical dose was 2 to 5 grams. (It should be noted this was a "total" dose; many regimens called for 3 doses daily over 3 days, and the "3 teaspoons 3 times a day for 3 days" regimen was typical around the 50's when use of santonin was starting to wane; actual doses per "dose" were closer to 20-30 milligrams per adult dose in a typical "50's regimen", but "one-shot" doses of santonin (especially via suppository) were common in the late 1800s-early 1900s.) The only formerly registered British preparation (as of 1911) was the "trochiscus santonini" (santonin lozenge), but the preparation "sodii santoninas" (soda of santonin) was also formerly listed as an official preparation in the U.S. Pharmacopeia. Commercial preparations containing santonin (usually containing a purgative laxative as well) also appeared in US drug formularies as late as the 50's; the "Modern Drug Encyclopedia and Therapeutic Index" of 1955 listed Lumbricide (produced by Massengill) and a generic santonin prepraration made by Winthrop-Stearns (now Winthrop-Sanofi).

Santonin also was used in a lesser extent in treatment of atony of the bladder. This usage largely dropped off after the early 1900s.

Dosage forms varied for santonin; in the 1800s-1900s, santonin lozenges or suppositories designed for single-dosage treatment of ascarid infestation were the typical form of treatment, whilst in the 50's the two remaining santonin preparations on the market in the United States were liquid medications.

Hazards and difficulty of use of santonin

Santonin was an agent which (compared to more modern anthelminthic drugs) was very complicated to use and entailed rather serious risk to the patient. Nearly every formulary and herbal which lists santonin or santonin-containing plants lists the real risk of yellow vision and of fatal reactions; even small doses of santonin cause disturbances of vision, usually yellow vision or perhaps green (xanthopsia or chromatopsia). Even the "Encyclopedia Britannica" noted:

...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.

More typical is the warning given regarding side effects of santonin in "King's American Dispensatory":

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.

At least one modern herbal has also noted these same severe side effects of santonin.

Even were it not for the fact that santonin is among the most toxic of herbal anthelminthic drugs, deworming using santonin is complicated in comparison to more modern anthelminthics. Typically, santonin must be taken whilst fasting completely (both before and after taking the drug) for "single dose" regimens or on a full stomach with all fats and oils in the diet being avoided for 2-3 days before treatment as well as during treatment and 2-3 days afterwards (due to santonin being fat soluble and having an increased risk of side effects); after a course of santonin, a purgative must be given to cleanse the body of the dead worms. (The two remaining registered santonin preparations in the United States as of 1955 were in fact santonin/purgative combinations; Lumbricide contained santonin and senna (among other ingredients) and the Winthrop-Stearns generic preparation was a santonin/cascara sagrada combination drug.)

Due to the severe side effects (even when used as directed), the need for a purgative, and the development of many safer deworming drugs, santonin has largely fallen out of use. Typically mebendazole and pyrantel pamoate are used in modern pharmacopoeia practice where santonin was formerly used; even guides on holistic medicine strongly recommend avoiding the use of santonin due to its severe and occasionally fatal side effects and the availability of far safer anthelminthics [http://www.indiangyan.com/books/healthbooks/complet_femily_medicine_book/Worm_infestations.shtml] . The Council Directive 65/65 European EconomicCommunity (EEC) (in regards to pharmaceuticals and naturopathic preparations) has officially ruled santonin preparations to have an "unacceptable" risk-benefit ratio and preparations containing santonin are no longer eligible for registration in EU countries [http://www.diahome.org/content/abstract/1996/dj304878.pdf] .

antonin and absinthe

While absinthe is certainly more infamous for its content of thujone [ [http://www.erowid.org/chemicals/absinthe/absinthe_faq.shtml Erowid.org] Absinthe FAQ] , the liquor does also contain small amounts of santonin Fact|date=August 2007 . It has been speculated by some parties that Impressionist art--in particular, Van Gogh's artwork--may have been inspired "not" by thujone and its presumed psychotropic effects, but on the "yellow vision" or xanthopsia which is a known side effect of santonin. This has been disputed, however, most notably by Arnold and Loftus (1991) who have noted the santonin content would have been insufficient to cause xanthopsia.

References