Cantharidin

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Cantharidin
Cantharidin-2D.svg
Cantharidin-3D.png
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 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 200-263-3
KEGG
PubChem CID
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+ Yes check.svgY
    Key: DHZBEENLJMYSHQ-YUMGAWCOSA-N Yes check.svgY
  • 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
Topical
Legal status
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Highly toxic
GHS labelling:
GHS-pictogram-skull.svg GHS-pictogram-exclam.svg
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.svgHealth 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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)
Cantharidin
Clinical data
Trade names Ycanth, others
License data
Routes of
administration 		Topical
Legal status
Legal status
Identifiers
DrugBank
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.240 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H12O4
Molar mass 196.202 g·mol−1

Cantharidin is an odorless, colorless fatty substance of the terpenoid class, which is secreted by many species of blister beetles. [a] Its main current use in pharmacology is treating molluscum contagiosum and 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, [4] is an odorless, colorless natural product with solubility in various organic solvents,[ specify ] but only slight solubility in water. [5] Its skeleton is tricyclic, formally, a tricyclo-[5.2.1.02,6]decane 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.

Biosynthesis from farnesol -- bonds to be formed and major atoms to be added are in @media screen{html.skin-theme-clientpref-night .mw-parser-output div:not(.notheme)>.tmp-color,html.skin-theme-clientpref-night .mw-parser-output p>.tmp-color,html.skin-theme-clientpref-night .mw-parser-output table:not(.notheme) .tmp-color{color:inherit!important}}@media screen and (prefers-color-scheme:dark){html.skin-theme-clientpref-os .mw-parser-output div:not(.notheme)>.tmp-color,html.skin-theme-clientpref-os .mw-parser-output p>.tmp-color,html.skin-theme-clientpref-os .mw-parser-output table:not(.notheme) .tmp-color{color:inherit!important}} blue; while bonds to be broken and atoms/structural segments to be removed are in red. Cantharidin biosynthesis2.png
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 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). [9]

History

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

Non-aphrodisiac uses

Pharmaco-chemical isolation

Cantharidin was first isolated as a chemically pure substance in 1810 by Pierre Robiquet, [23] 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 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. [5] Beetles feed on weeds, 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 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 ingested by humans, the LD50 is unknown, but fatal doses have been recorded between 10 mg and 65 mg [38] . The median lethal dose appears to be around 1 mg/kg [39] but individuals have survived after consuming oral doses as high as 175 mg [40] . Ingesting cantharidin can initially cause severe damage to the lining of the gastrointestinal and urinary tracts, and may also cause permanent renal damage. Symptoms of cantharidin poisoning include blood in the urine, abdominal pain, and (rarely) prolonged erections. [36]

Risks of aphrodisiac use

The extreme toxicity of cantharidin makes any use as an aphrodisiac highly dangerous. [41] [42] 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 epidermal cells, causing the release of serine proteases, enzymes that break the 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. [43] [44]

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. [45]

Bioactivities

Cantharidin appears to have some effect in the topical treatment of cutaneous leishmaniasis in animal models. [46] In addition to topical medical applications, cantharidin and its analogues may have activity against cancer cells. [47] [48] [49] Laboratory studies with cultured tumor cells suggest that this activity may be the result of PP2A inhibition. [50] [51]

Notes

  1. ↑ Including broadly in genus Epicauta , genus Berberomeloe , and in species Lytta vesicatoria (Spanish fly). False blister beetles, cardinal beetles, and soldier beetles also produce cantharidin.

Related Research Articles

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<span class="mw-page-title-main">Molluscum contagiosum</span> Viral infection of the skin

Molluscum contagiosum (MC), sometimes called water warts, is a viral infection of the skin that results in small raised pink lesions with a dimple in the center. They may become itchy or sore, and occur singularly or in groups. Any area of the skin may be affected, with abdomen, legs, arms, neck, genital area, and face being the most common. Onset of the lesions is around seven weeks after infection. They usually go away within a year without scarring.

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<span class="mw-page-title-main">Blister beetle</span> Family of beetles

Blister beetles are beetles of the family Meloidae, so called for their defensive secretion of a blistering agent, cantharidin. About 7,500 species are known worldwide. Many are conspicuous and some are aposematically colored, announcing their toxicity to would-be predators.

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Molluscum contagiosum virus (MCV) is a species of DNA poxvirus that causes the human skin infection molluscum contagiosum. Molluscum contagiosum affects about 200,000 people a year, about 1% of all diagnosed skin diseases. Diagnosis is based on the size and shape of the skin lesions and can be confirmed with a biopsy, as the virus cannot be routinely cultured. Molluscum contagiosum virus is the only species in the genus Molluscipoxvirus. MCV is a member of the subfamily Chordopoxvirinae of family Poxviridae. Other commonly known viruses that reside in the subfamily Chordopoxvirinae are variola virus and monkeypox virus.

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References

  1. ↑ "Ycanth- cantharidin solution". DailyMed. 25 July 2023. Archived from the original on 29 August 2023. Retrieved 28 August 2023.
  2. ↑ "FDA approves first treatment for molluscum contagiosum". FDA. 24 July 2023.
  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. 1 2 3 Schmitz DG (2013). "Overview of Cantharidin Poisoning (Blister Beetle Poisoning)". In Aiello SE, Moses MA (eds.). The Merck Veterinary Manual. Kenilworth, NJ, USA: Merck Sharp & Dohme. ISBN   978-0911910612. Archived from the original on 22 December 2015. Retrieved 14 December 2015.
  6. ↑ Petroski RJ, McCormick SP, eds. (2012). Secondary-Metabolite Biosynthesis and Metabolism. Springer Science & Business Media. ISBN   978-0-306-44309-1.
  7. ↑ Jiang M, Lü S, Zhang Y (January 2017). "The Potential Organ Involved in Cantharidin Biosynthesis in Epicauta chinensis Laporte (Coleoptera: Meloidae)". Journal of Insect Science. 17 (2): 52. doi:10.1093/jisesa/iex021. PMC   5633858 . PMID   28423415.
  8. ↑ Capinera JL, Gardner DR, Stermitz FR (1985). "Cantharidin Levels in Blister Beetles (Coleoptera: Meloidae) Associated with Alfalfa in Colorado". Journal of Economic Entomology. 78 (5): 1052–1055. doi:10.1093/jee/78.5.1052.
  9. ↑ Bravo C, Mas-Peinado P, Bautista LM, Blanco G, Alonso JC, García-París M (2017). "Cantharidin is conserved across phylogeographic lineages and present in both morphs of Iberian Berberomeloe blister beetles (Coleoptera, Meloidae)". Zoological Journal of the Linnean Society. 180 (4): 790–804. doi:10.1093/zoolinnean/zlw016. 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
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  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. ↑ Milsten R (2000). The Sexual Male: Problems and Solutions. W. W. Norton & Company. p. 170. ISBN   978-0-393-32127-2.
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  17. ↑ Jacques Levron, Le Maréchal de Richelieu, un libertin fastueux (Paris, Perrin, 1971).
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  35. 1 2 Karras DJ, Farrell SE, Harrigan RA, Henretig FM, Gealt L (September 1996). "Poisoning from "Spanish fly" (cantharidin)". The American Journal of Emergency Medicine. 14 (5): 478–483. doi:10.1016/S0735-6757(96)90158-8. 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. 1 2 Binder R (May 1979). "Malpractice--in dermatology". Cutis. 23 (5): 663–666. 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. ↑ Moed L, Shwayder TA, Chang MW (2001). "Cantharidin Revisited". Archives of Dermatology. 137 (10): 1357–1360. doi:10.1001/archderm.137.10.1357. PMID   11594862.
  39. ↑ OAKS WW, DITUNNO JF, MAGNANI T, LEVY HA, MILLS LC (1960). "Cantharidin poisoning". Archives of Internal Medicine. 105 (4): 574–582. doi:10.1001/archinte.1960.00270160072009. PMID   14428136.
  40. ↑ Matsuzawa M, Graziano MJ, Casida JE (1987). "Endothal and cantharidin analogs: Relation of structure to herbicidal activity and mammalian toxicity". Journal of Agricultural and Food Chemistry. 35 (5): 823–829. Bibcode:1987JAFC...35..823M. doi:10.1021/jf00077a045.
  41. ↑ Shamloul R (January 2010). "Natural aphrodisiacs". The Journal of Sexual Medicine. 7 (1 Pt 1): 39–49. doi:10.1111/j.1743-6109.2009.01521.x. PMID   19796015.
  42. ↑ Sandroni P (October 2001). "Aphrodisiacs past and present: a historical review". Clinical Autonomic Research. 11 (5): 303–307. doi:10.1007/BF02332975. PMID   11758796. 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.
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