Santonin
Encyclopedia
Santonin is a drug
which was widely used in the past as an anthelminthic, a drug that expels parasitic worm
s (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 ascaricide
s and is no longer registered as a drug in most countries.
(C15H20O4) via based-catalyzed hydrolysis
followed by a multistep rearrangement process.
Santonin dissolves in alkalies with formation of salt
s 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".
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.
lumbricoides and in ascarid parasitoses in general (including threadworm parasitosis). It is ineffective in treatment of tapeworm infestation.
The Encyclopædia 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 '50s when use of santonin was starting to wane; actual doses per dose were closer to 20-30 milligrams per adult dose in a typical "'50s regimen", but "one-shot" doses of santonin (especially via suppository) were common in the late 19th century-early 20th century.) 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. Pharmacopoeia. Commercial preparations containing santonin (usually containing a purgative laxative as well) also appeared in US drug formularies as late as the '50s; the Modern Drug Encyclopedia and Therapeutic Index of 1955 listed Lumbricide (produced by Massengill) and a generic santonin preparation 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 20th century.
Dosage forms varied for santonin; in the 19th-20th centuries, 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.
or chromatopsia). Even the Encyclopædia Britannica noted:
More typical is the warning given regarding side effects of santonin in King's American Dispensatory:
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 Economic
Community (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.
is certainly more infamous for its content of thujone
, the liquor does also contain small amounts of santonin . 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.
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
which was widely used in the past as an anthelminthic, a drug that expels parasitic worm
Worm
The term worm refers to an obsolete taxon used by Carolus Linnaeus and Jean-Baptiste Lamarck for all non-arthropod invertebrate animals, and stems from the Old English word wyrm. Currently it is used to describe many different distantly-related animals that typically have a long cylindrical...
s (helminths) from the body, by either killing or stunning them. Santonin was formerly listed in U.S. and British
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
pharmacopoeia
Pharmacopoeia
Pharmacopoeia, pharmacopeia, or pharmacopoea, , in its modern technical sense, is a book containing directions for the identification of samples and the preparation of compound medicines, and published by the authority of a government or a medical or pharmaceutical society.In a broader sense it is...
but has fallen out of use with the development of safer ascaricide
Ascaricide
Ascaricides are drugs to treat ascariasis that is caused by infections with parasitic nematodes of the genus Ascaris...
s and is no longer registered as a drug in most countries.
Reactions and properties
Santonin can be converted to santonic acidSantonic acid
Santonic acid is an organic compound containing both carboxylic acid and ketone functionality.It was synthesized from santonin by base-mediated hydrolysis of a lactone followed by a multistep rearrangement process by R. B. Woodward....
(C15H20O4) via based-catalyzed hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
followed by a multistep rearrangement process.
Santonin dissolves in alkalies with formation of salt
Salt
In chemistry, salts are ionic compounds that result from the neutralization reaction of an acid and a base. They are composed of cations and anions so that the product is electrically neutral...
s of this carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
. Santonin, in acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
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
Ethyl group
In chemistry, an ethyl group is an alkyl substituent derived from ethane . It has the formula -C2H5 and is very often abbreviated -Et.Ethylation is the formation of a compound by introduction of the ethyl functional group, C2H5....
ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
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
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
, chloroform
Chloroform
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...
and boiling water. It is derived from santonica (the unexpanded flower-heads
Head (botany)
The capitulum is considered the most derived form of inflorescence. Flower heads found outside Asteraceae show lesser degrees of specialization....
of Artemisia maritima var. stechmanniana). Others refer to A. cina
Artemisia cina
Artemisia cina, commonly known as santonica , Levant wormseed, and wormseed, is an herbaceous perennial of the daisy family. Its dried flowerheads are the source of the vermifugic drug santonin since ancient times. Its common names arise from its known ability to expel worms...
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
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
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".
Proposed Biosynthesis
The full biosynthesisBiosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
of α-santonin has not been elucidated but α-santonin bears much similarity to parthenolide
Parthenolide
Parthenolide is a sesquiterpene lactone of the germacranolide class which occurs naturally in the plant feverfew , after which it is named. It is found in highest concentration in the flowers and fruit....
. The proposed biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
begins with the cyclization of farnesyl diphosphate (FPP) to (+)-germacrene
Germacrene
Germacrenes are a class of volatile organic hydrocarbons, specifically, sesquiterpenes. Germacrenes are typically produced in a number plant species for their antimicrobial and insecticidal properties, though they also play a role as insect pheromones...
A by a sesquiterpene synthase. (+)-germacrene
Germacrene
Germacrenes are a class of volatile organic hydrocarbons, specifically, sesquiterpenes. Germacrenes are typically produced in a number plant species for their antimicrobial and insecticidal properties, though they also play a role as insect pheromones...
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.
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 AscarisAscaris
Ascaris is a genus of parasitic nematode worms known as the "giant intestinal roundworms". One species, A. suum, typically infects pigs, while another, A. lumbricoides, affects human populations, typically in sub-tropical and tropical areas with poor sanitation. A...
lumbricoides and in ascarid parasitoses in general (including threadworm parasitosis). It is ineffective in treatment of tapeworm infestation.
The Encyclopædia 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 '50s when use of santonin was starting to wane; actual doses per dose were closer to 20-30 milligrams per adult dose in a typical "'50s regimen", but "one-shot" doses of santonin (especially via suppository) were common in the late 19th century-early 20th century.) 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. Pharmacopoeia. Commercial preparations containing santonin (usually containing a purgative laxative as well) also appeared in US drug formularies as late as the '50s; the Modern Drug Encyclopedia and Therapeutic Index of 1955 listed Lumbricide (produced by Massengill) and a generic santonin preparation 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 20th century.
Dosage forms varied for santonin; in the 19th-20th centuries, 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 (xanthopsiaXanthopsia
Xanthopsia refers to the predominance of yellow in vision due to a yellowing of the optic media of the eye. The most common cause is digoxin toxicity and the development of cataracts which can cause a yellow filtering effect....
or chromatopsia). Even the Encyclopædia Britannica noted:
...These effects usually pass off in a few days. Large doses, however, produce toxic effects, aphasiaAphasiaAphasia is an impairment of language ability. This class of language disorder ranges from having difficulty remembering words to being completely unable to speak, read, or write....
, muscular tremors and epileptiform convulsions, and the disturbances of vision may go on to total blindnessBlindnessBlindness is the condition of lacking visual perception due to physiological or neurological factors.Various scales have been developed to describe the extent of vision loss and define 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 RoseEdmund RoseEdmund Rose was a German surgeon who was a native of Berlin. He studied medicine in Berlin and Würzburg and subsequently was an assistant to surgeon Robert Ferdinand Wilms in Berlin from 1860 until 1864...
, 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
Mebendazole
Mebendazole or MBZ is a benzimidazole drug developed by Janssen Pharmaceutica and marketed as Vermox, Ovex, Antiox, and Pripsen...
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 Economic
Community (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.
Santonin and absinthe
While absintheAbsinthe
Absinthe is historically described as a distilled, highly alcoholic beverage. It is an anise-flavoured spirit derived from herbs, including the flowers and leaves of the herb Artemisia absinthium, commonly referred to as "grande wormwood", together with green anise and sweet fennel...
is certainly more infamous for its content of thujone
Thujone
Thujone is a ketone and a monoterpene that occurs naturally in two diastereomeric forms: -α-thujone and -β-thujone. It has a menthol odor. Even though it is best known as a chemical compound in the spirit absinthe, recent tests show absinthe contains only small quantities of thujone, and may or may...
, the liquor does also contain small amounts of santonin . 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
Xanthopsia
Xanthopsia refers to the predominance of yellow in vision due to a yellowing of the optic media of the eye. The most common cause is digoxin toxicity and the development of cataracts which can cause a yellow filtering effect....
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.