Cantharidin

Source: Wikipedia, the free encyclopedia.

Cantharidin
Names
Preferred IUPAC name
(3aR,4S,7R,7aS)-3a,7a-Dimethylhexahydro-4,7-epoxy[2]benzofuran-1,3-dione
Other names
  • Cantharidin
  • Spanish fly
  • Ycanth
Identifiers
3D model (
JSmol
)
85302
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard
 100.000.240 Edit this at Wikidata
EC Number
  • 200-263-3
KEGG
UNII
  • InChI=1S/C10H12O4/c1-9-5-3-4-6(13-5)10(9,2)8(12)14-7(9)11/h5-6H,3-4H2,1-2H3/t5-,6+,9-,10+ checkY
    Key: DHZBEENLJMYSHQ-YUMGAWCOSA-N checkY
  • O=C2OC([C@@]1(C)[C@@H]3CC[C@@H](O3)[C@]12C)=O
Properties
C10H12O4
Molar mass 196.202 g·mol−1
Density 1.41 g/cm3
Melting point 212 °C (414 °F; 485 K)
Pharmacology
None
Legal status
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Highly toxic
GHS labelling:
GHS06: Toxic GHS07: Exclamation mark
Danger
H300, H315, H319, H335
P261, P264, P270, P271, P280, P301+P310, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, P501
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 4: Very short exposure could cause death or major residual injury. E.g. VX gasFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazards (white): no code
4
1
1
Lethal dose or concentration (LD, LC):
0.03–0.5 mg/kg (human)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Cantharidin
Clinical data
Trade namesYcanth, others
License data
Topical
Legal status
Legal status
Identifiers
ECHA InfoCard
100.000.240 Edit this at Wikidata
Chemical and physical data
FormulaC10H12O4
Molar mass196.202 g·mol−1

Cantharidin is an odorless, colorless fatty substance of the

warts topically.[2] It is a burn agent and poisonous in large doses, and has been historically used as aphrodisiacs (Spanish fly
). In its natural form, cantharidin is secreted by the male blister beetle, and given to the female as a copulatory gift during mating. Afterwards, the female beetle covers her eggs with it as a defense against predators.

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 chemical burns. 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.[3]

Chemistry

Structure and nomenclature

Cantharidin, from the Greek kantharis, for beetle,

bicyclic
ring system.

Biosynthesis from farnesol ⁠— ⁠bonds to be formed and major atoms to be added are in blue; while bonds to be broken and atoms/structural segments to be removed are in red.

The complete mechanism of the biosynthesis of cantharidin is unknown. Its framework formally consists of two isoprene units.[6] 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.[7]

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.[8]

Males of

haemolymph is also higher in males (80.9 ± 106.5 µg/g) than in females (20.0 ± 41.5 µg/g).[9]

History

Lytta vesicatoria (a.k.a "Spanish fly"), a beetle that secretes cantharidin.

Aphrodisiac preparations

Preparations made from blister beetles (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,[10] and because they can cause prolonged erection or priapism in men.[11] 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
    Augustus Caesar, to entice members of the imperial family or dinner guests to commit sexual indiscretions (thus, providing her information to hold over them).[12]
  • The German emperor Henry IV (1050–1106) is said to have consumed cantharides.[13]
  • The French surgeon Ambroise Paré (1510–1590) described a case in 1572 of a man suffering from “the most frightful satyriasis” after taking a potion composed of nettles and a cantharid extract.[14] This is perhaps the same man of whom Paré relates that a courtesan sprinkled a cantharid powder on food she served to him, after which the man experienced "violent priapism" and anal bleeding, of which he later died. Paré also cites the case of a priest who died of hematuria after swallowing a dose of cantharides, which he intended to fortify his sex drive.[15]
  • 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.[15]
  • The French sorceress Catherine Monvoisin (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.[16]
  • Aphrodisiac sweets presumably laced with cantharides were circulated within
    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.[15][17]
  • The French writer Donatien Alphonse François ⁠— ⁠notoriously known as the
    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.[18][19]

Non-aphrodisiac uses

Pharmaco-chemical isolation

Cantharidin was first isolated as a chemically pure substance in 1810 by

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 blistering properties 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.[24]

Other uses of the pharmacological isolate

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.

baled hay, e.g., a single flake (4–5 in. section[29]) may have several hundred insects, or none at all.[5] Horses are very sensitive to the cantharidin produced by beetle infestations: the LD50 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.[30]

Great bustards, a strongly polygynous bird species,[31] are not immune to the toxicity of cantharidin; they become intoxicated after ingesting blister beetles. However, cantharidin has activity also against parasites that infect them.[32][33] Great bustards may eat toxic blister beetles of the genus Meloe to increase the sexual arousal of males.[34]

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.[35] However, this references unregulated sources of cantharidin.[36] In July 2023, the US FDA approved a topical formulation of cantharidin (Ycanth) for the treatment of molluscum contagiosum.[37]

When

renal damage. Symptoms of cantharidin poisoning include blood in the urine, abdominal pain, and rarely prolonged erections.[36]

Risks of aphrodisiac use

Main article: Spanish fly

The extreme toxicity of cantharidin makes any use as an aphrodisiac highly dangerous.[38][39] As a result, it is illegal to sell (or use) cantharidin or preparations containing it without a prescription in many countries.[35]

Research

Mechanism of action

Topical cantharidin is absorbed by the lipid membranes of

peptide bonds in proteins. This causes the disintegration of desmosomal plaques, cellular structures involved in cell-to-cell adhesion, leading to detachment of the tonofilaments 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.[40][41]

Pharmaceutical use

VP-102, an experimental drug-device combination that includes cantharidin delivered via a single-use applicator, is being studied for the treatment of molluscum contagiosum, common warts, and genital warts.[42]

Bioactivities

Cantharidin appears to have some effect in the topical treatment of cutaneous leishmaniasis in animal models.[43] In addition to topical medical applications, cantharidin and its analogues may have activity against cancer cells.[44][45][46] Laboratory studies with cultured tumor cells suggest that this activity may be the result of

PP2A inhibition.[47][48]

Notes

  1. soldier beetles
    also produce cantharidin.

References

  1. ^ "Ycanth- cantharidin solution". DailyMed. 25 July 2023. Archived from the original on 29 August 2023. Retrieved 28 August 2023.
  2. ^ https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-molluscum-contagiosum
  3. ^ As defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002). See "40 C.F.R.: Appendix A to Part 355—The List of Extremely Hazardous Substances and Their Threshold Planning Quantities" Archived 25 February 2012 at the Wayback Machine (PDF) (1 July 2008 ed.). U.S. Government Printing Office. Retrieved 29 October 2011.
  4. ^ A Dictionary of Entomology. CABI. 2011. p. 253.
  5. ^
    ISBN 978-0911910612. Archived from the original
    on 22 December 2015. Retrieved 14 December 2015.
  6. ISBN 978-0-306-44309-1
    .
  7. PMID 28423415
    .
  8. doi:10.1093/jee/78.5.1052
    .
  9. hdl:10261/153832
    .
  10. ^ John L. Capinera, Encyclopedia of Entomology, Volume 4, Springer Science & Business Media, 2008. p.2010
  11. ^ Peter V. Taberner, Aphrodisiacs: The Science and the Myth, Springer Science & Business Media, 2012, pp.100ff
  12. ISBN 978-0-345-40102-1
    .
  13. ^ Eplett L (13 March 2012). "When Sparks Fly: Aphrodisiacs and the Fruit Fly". Scientific American. Archived from the original on 29 November 2014. Retrieved 18 November 2014.
  14. ISBN 978-0-393-32127-2
    .
  15. ^ a b c Cabanès A (1910). Remèdes d'autrefois. Paris: A. Maloine. p. 498.
  16. ^ Richard Cavendish, The Black Arts (London: Pan Books, 1969), p. 333.
  17. ^ Jacques Levron, Le Maréchal de Richelieu, un libertin fastueux (Paris, Perrin, 1971).
  18. ISBN 978-0-394-54797-8
    .
  19. ^ Schaeffer N (2000). The Marquis de Sade: A Life. Cambridge, MA, USA: Harvard University Press. p. 58.
  20. ^ Covarrubias-Horozco S (2006). Tesoros de la lengua castellana o española. Universidad de Navarra - Iberoamericana - Vervuert.
  21. ^ Closs JF (1767). A New Method of Curing the Small-pox ... with a Specimen of Miscellaneous Observations on Medical Subjects; from the Latin ... by a Physician. Hawes. Archived from the original on 14 January 2023. Retrieved 15 April 2017. Cantharides referred to throughout the book.
  22. ^ Andrew Taylor Still, The philosophy and mechanical principles of osteopathy, 1892, chapter 12: "Smallpox". The 1902 edition is available here Archived 14 July 2019 at the Wayback Machine.
  23. ISBN 978-3432978925
    .
  24. ^ Robiquet PJ (1810). "Expériences sur les cantharides". Annales de Chimie. 76: 302–322.
  25. PMID 13519856
    .
  26. PMID 16127954. Archived from the original
    on 9 July 2008. Retrieved 2 December 2012.
  27. ^ "Molluscum contagiosum". Merck Manuals. November 2005. Archived from the original on 18 October 2007. Retrieved 21 October 2007.
  28. ISBN 978-1-56718-329-0
    .
  29. ISBN 978-1305537651
    . Retrieved 14 December 2015.
  30. ^ "Blister Beetle Poisoning / Cantharidin toxicosis". Archived from the original on 26 June 2010. Retrieved 31 December 2010.
  31. S2CID 8741416
    .
  32. PMID 25337911
    .
  33. PMID 22001622
    .
  34. S2CID 17325635
    .
  35. ^
    PMID 8765116
    . While most commonly available preparations of Spanish fly contain cantharidin in negligible amounts, if at all, the chemical is available illicitly in concentrations capable of causing severe toxicity. Symptoms of cantharidin poisoning include burning of the mouth, dysphagia, nausea, hematemesis, gross hematuria, and dysuria. Mucosal erosion and hemorrhage is seen in the upper gastrointestinal (GI) tract. Renal dysfunction is common and related to acute tubular necrosis and glomerular destruction.
  36. ^
    PMID 456036
    .
  37. ^ "FDA approves first treatment for molluscum contagiosum". U.S. Food and Drug Administration. 24 July 2023. Archived from the original on 11 August 2023. Retrieved 6 August 2023.
  38. PMID 19796015
    .
  39. S2CID 32348540
    . Cantharidin ("Spanish fly") is a chemical with vesicant properties derived from blister beetles, which has been used for millennia as a sexual stimulant by both sexes. Its mode of action is by inhibition of phosphodiesterase and protein phosphatase activity and stimulation of β-receptors, inducing vascular congestion and inflammation. Morbidity from its abuse is significant. The gastrointestinal tract sustains the brunt of toxicity, resulting in fatal hemorrhages. Renal toxicity is a result of its renal excretion, which may lead to acute tubular necrosis. Cardiac effects are most likely due to hemorrhagic shock, but they also can be due to myofibril degeneration, mitochondrial swelling, and pericardial and subendocardial hemorrhages.
  40. PMID 11594862
    .
  41. S2CID 45714898
    .
  42. ^ "Verrica Pharmaceuticals Announces Extension of FDA Review Period of its NDA for VP-102 for the Treatment of Molluscum Contagiosum". drugs.com. 28 May 2021. Archived from the original on 24 June 2021. Retrieved 24 June 2021.
  43. PMID 20435039
    .
  44. PMID 21658450
    .
  45. PMID 12970086
    .
  46. PMID 20875681
    .
  47. S2CID 38088568
    .
  48. S2CID 24345174
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Cantharidin&oldid=1214590203"