Cantharidin is an odorless, colorless fatty substance of the terpenoid class, which is secreted by many species of . Its main current use in pharmacology is treating molluscum contagiosum and warts topically.
Poisoning from cantharidin is a significant veterinary concern, especially in horses, but it can also be poisonous to humans if taken internally (where the source is usually experimental self-exposure). Externally, cantharidin is a potent vesicant (blistering agent), exposure to which can cause severe . Properly dosed and applied, the same properties have also been used therapeutically, for instance, for treatment of skin conditions, such as molluscum contagiosum infection of the skin.
Cantharidin is classified as an extremely hazardous substance in the United States, and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.[As defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002). See ]
Chemistry
Structure and nomenclature
Cantharidin, from the Greek
kantharis, for beetle,
is an odorless, colorless
natural product with solubility in various organic solvents, but only slight solubility in water.
Its skeleton is
tricyclic, formally, a tricyclo-5.2.1.0
2,6decane skeleton. Its functionalities include a carboxylic acid anhydride (−CO−O−CO−) substructure in one of its rings, as well as a bridging
ether in its
bicyclic ring system.
Distribution and availability
The level of cantharidin in blister beetles can be quite variable. Among blister beetles of the genus
Epicauta in
Colorado,
E. pennsylvanica contains about 0.2 mg,
E. maculata contains 0.7 mg, and
E. immaculata contains 4.8 mg per beetle; males also contain higher levels than females.
Males of Berberomeloe majalis have higher level of cantharidin per beetle: 64.22 ± 51.28 mg/g (dry weight) and 9.10 ± 12.64 mg/g (d. w.). Cantharidin content in haemolymph is also higher in males (80.9 ± 106.5 μg/g) than in females (20.0 ± 41.5 μg/g).
Laboratory synthesis
There have been multiple synthetic approaches to achieve cantharidin in the lab. A common strategy employed by different total synthesis methods is to begin with a
Diels-Alder cycloaddition reaction to form the six-membered ring.
The starting material often utilizes a furan as the diene, giving the formation of a bicyclic ring.
Biosynthesis
The complete mechanism of the
biosynthesis of cantharidin is unknown. Its framework formally consists of two
isoprene units.
However,
feeding studies indicate that the biosynthetic process is more complicated, and not a simple product of geranyl pyrophosphate or related ten-carbon parent structure, as the seeming
monoterpene nature would suggest. Instead, there is a
farnesol (15-carbon) precursor from which certain carbon segments are later excised.
Biosynthesis utilizing farnesol as a key intermediate is further supported by experiments in which key genes whose transcripts are expected to participate in the biosynthesis pathway were interfered with by RNA interference methods. The mevalonate pathway (MVA pathway) is responsible for producing isoprenoids in many organisms, including farnesol.
History
Aphrodisiac preparations
Preparations made from
(particularly "Spanish fly") have been used since ancient times as an
aphrodisiac, possibly because their physical effects were perceived to mimic those of sexual arousal,
[John L. Capinera, Encyclopedia of Entomology, Volume 4, Springer Science & Business Media, 2008. p.2010] and because they can cause prolonged erection or
priapism in men.
[Peter V. Taberner, Aphrodisiacs: The Science and the Myth, Springer Science & Business Media, 2012, pp.100ff] These preparations were known as
cantharides, from the Greek word for "beetle".
Examples of such use found in historical sources include:
-
The ancient Roman historian Tacitus relates that a cantharid preparation was used by the empress Livia, wife of Augustus Caesar, to entice members of the imperial family or dinner guests to commit sexual indiscretions (thus, providing her information to hold over them).
-
The German emperor Henry IV (1050–1106) is said to have consumed cantharides.
-
The French surgeon Ambroise Paré (1510–1590) described a case in 1572 of a man suffering from "the most frightful hypersexuality" after taking a potion composed of Urtica dioica and a cantharid extract.
-
Cantharides were in widespread use among the upper classes in France in the 1600s, despite being a banned substance. Police searches in connection with a rash of poisonings around 1680 turned up many stashes of "bluish flies", which were known to be used in the preparation of aphrodisiac potions.
-
The French sorceress La Voisin (known as "La Voisin," c. 1640–1680) was recorded in the 1670s as having prepared a love charm made from Spanish fly mixed with dried mole's blood and bat's blood.
[Richard Cavendish, The Black Arts (London: Pan Books, 1969), p. 333.]
-
Aphrodisiac sweets presumably laced with cantharides were circulated within libertine circles during the 1700s in France. They were multicolored tablets nicknamed "pastilles de Richelieu," after the Maréchal de Richelieu, a notorious libertine (not to be confused with his great-uncle, the Cardinal Richelieu) who procured sexual encounters for King Louis XV.
[Jacques Levron, Le Maréchal de Richelieu, un libertin fastueux (Paris, Perrin, 1971).]
-
The French writer Donatien Alphonse François — notoriously known as the Marquis de Sade (1740–1814) — is said to have given aniseed-flavored pastilles laced with Spanish fly to two prostitutes at a pair of orgies in 1772, poisoning and nearly killing them. He was sentenced to death for that (and for the crime of sodomy), but was later reprieved on appeal.
Non-aphrodisiac uses
-
The Spanish clergyman Juan de Horozco y Covarrubias (es) (c. 1540–1610) reported the use of blister beetles as a poison as well as an aphrodisiac.
-
Preparations of dried blister beetles were at one time used as a treatment for smallpox.
[ Cantharides referred to throughout the book.] As late as 1892, Andrew Taylor Still, the founder of osteopathy, recommended inhaling a tincture of cantharidin as an effective preventative and treatment for smallpox, decrying vaccination.
-
Japanese ninja used blister beetles combined with arsenic to create a noxious gas.
Pharmaco-chemical isolation
Cantharidin was first isolated as a chemically pure substance in 1810 by
Pierre Robiquet,
a French chemist then living in
Paris. Robiquet isolated cantharidin as the active ingredient in pharmacological preparations of
Lytta vesicatoria, a.k.a. "Spanish fly", a species of
blister beetle. This was one of the first historical instances of the identification and extraction of a simple active principle from a complex medicine.
Robiquet found cantharidin to be an odorless and colorless solid at room temperature. He demonstrated that it was the active principle responsible for the aggressively blister agent of the coating of the eggs of the blister beetle, and additionally established that cantharidin had toxic properties comparable in degree to those of the most virulent poisons known in the 19th century, such as strychnine.
Other uses of the pharmacological isolate
-
Diluted solutions of cantharidin can be used as a topical medication to remove
-
In Santería rituals, cantharides are used in incense.
Veterinary issues
Poisoning by
Epicauta species from cantharidin is a significant veterinary concern, especially in horses; species infesting feedstocks depend on region—e.g.,
Epicauta pennsylvanica (black blister beetle) in the U.S. midwest; and
E. occidentalis, temexia, and vittata species (striped blister beetles) in the U.S. southwest—where the concentrations of the agent in each can vary substantially.
[ Beetles feed on , and occasionally move into crop fields used to produce livestock feeds (e.g., alfalfa), where they are found to cluster and find their way into hay bale, e.g., a single flake (4–5 in. section][ Horses are very sensitive to the cantharidin produced by beetle infestations: the for horses is roughly 1 mg/kg of the horse's body weight. Horses may be accidentally poisoned when fed bales of fodder with blister beetles in them.]
, a strongly polygynous bird species,
Human medical issues
General risks
As a blister agent, cantharidin has the potential to cause adverse effects when used medically; for this reason, it has been included in a list of "problem drugs" used by dermatologists and emergency personnel.[ ] In July 2023, the US FDA approved a topical formulation of cantharidin (Ycanth) for the treatment of molluscum contagiosum.
When ingestion by humans, the is unknown, but fatal doses have been
recorded between 10 mg and 65 mg.
Risks of aphrodisiac use
The extreme toxicity of cantharidin makes any use as an aphrodisiac highly dangerous.[
]
Research
Mechanism of action
Topical cantharidin is absorbed by the lipid membranes of Epidermis, causing the release of serine proteases, enzymes that break the peptide bonds in proteins. This causes the disintegration of Desmosome, cellular structures involved in cell-to-cell adhesion, leading to detachment of the Tonofibril that hold cells together. The process leads to the loss of cellular connections (acantholysis), and ultimately results in blistering of the skin. Lesions heal without scarring.
Pharmaceutical use
VP-102, an experimental drug-device combination that includes cantharidin delivered via a single-use applicator, was studied for the treatment of molluscum contagiosum, wart, and .
Toxicity
The liver, primarily responsible for metabolism and detoxification, often becomes damaged in cases of cantharidin poisoning. The hepatotoxicity of cantharidin arises from its inhibition of hepatocyte proliferation pathways, the promotion of hepatocyte apoptosis or autophagy, and increased inflammation.
Bioactivities
Cantharidin appears to have some effect in the topical treatment of cutaneous leishmaniasis in animal models.
Recent research has identified many other pathways in cancer cells that may be interfered with by cantharidin. Generally, cantharidin's anticancer targets include numerous transcription factors, protein kinases, growth factors, and inflammatory cytokines.
Notes
External links
