Lytta Vesicatoria (Spanish Fly) - Spanish Fly Drug

Lytta vesicatoria or Spanish fly is an emerald-green beetle in the family Meloidae, with approximate dimensions of 5 mm (0.20 in) wide by 20 mm (0.79 in) long. The genus and species names derive from the Greek lytta for rage, and the vesica for blister. It is one of a number of species that are collectively called blister beetles; it and other such species were used in preparations offered by traditional apothecaries, often referred to as Spanish fly. L. vesicatoria is sometimes called Cantharis vesicatoria, although the genus Cantharis is in an unrelated family, Cantharidae.

The terms Spanish fly and cantharides are synonymous and are used, the latter in particular, to refer to dried insects of this species, and related preparations. Cantharides derives from the Greek kantharis for beetle, and eidos, meaning form or shape. Although formerly taken internally, for use as a diuretic, and for supposed aphrodisiac effects, and externally as a rubifacient, counterirritant, and vesicant, cantharide preparations are poisonous, taken internally at large doses, and can lead to human and animal fatalities. Poisoning by Spanish fly/cantharides is a significant veterinary issue; ingestion of beetles or their extractsâ€"e.g., in infested hay or contaminated waterâ€"results periodically in serious toxic symptoms and the need for veterinary intervention, especially, in the U.S., in horses. Other specific cases of animal poisoning have been described: cattle in Africa with diarrhea and nephritis as a result of drinking contaminated water.

The perceived aphrodisiac properties of L. vesicatoria and its dried cantharides preparations are a result of its toxicology, specifically, irritant effects it has upon the body's genitourinary tract, although such views of this property are anachronistic alongside modern statements that the effect is painful and without pleasure. Moreover, seeking this outcome requires ingestion of the blister beetle preparation, and these, and preparations available illicitly in particular, can contain high concentrations of active agent that result in severe toxicity (poisoning). Human poisoning consequences include oral, gastrointestinal (GI), rectal, and vaginal tissue irritation through to severe GI hemorrhaging and kidney dysfunction, organ failure, and death. Clinical and postmortem examinationâ€"e.g., by endoscopy and autopsyâ€"reveal the destruction, as do laboratory findings of hematuria, proteinuria, and other reflections of the underlying pathologies. Management of cantharidin poisoning is only supportive.

Preparations from L. vesicatoria and other species have been the sources from which a pure natural compound (naturally derived chemical compound) called cantharidin has been isolated, which is largely responsible for the pharmacologic activities described. To add to confusion with nomenclature, the isolated molecule, cantharidin itself, is sometimes also referred to as "Spanish fly".

Description

Lytta vesicatoria is a "slender, soft-bodied metallic golden-green beetle," and so a Coleopteran. The beetle is described as being approximately 5 mm (0.20 in) wide by 20 mm (0.79 in) long.

Range and habitat

It is mainly described as southern European species although its range of habitats is more completely described as being "[t]hroughout southern Europe and eastward to Central Asia and Siberia," alternatively as being throughout Europe, and parts of northern and southern Asia (excluding China).

Adult beetles primarily feed on leaves of ash, lilac, amur privet, honey suckle and white willow tree while occasionally being found on plum, rose, and elm. The beetle reproductive cycle begins when eggs are laid in the vicinity of a ground-nesting host bee's nest. The beetles then develop through a very active first larval instar (the triangulin) that crawls into the host's nest and parasitizes it; the hypermetamorphosis-type of development then has remaining larval instar stages that are grub-like, and sedentary.

Active agent

Cantharidin, the principal active component in preparations of Lytta vesicatoria-derived Spanish fly, was first isolated and named in 1810 by Pierre Robiquet, a French chemist living in Paris, who demonstrated that it was the principle agent responsible for the aggressively blistering properties of this insect's egg coating; toxicity comparable in degree to that of the most violent poisons known in the 19th century, such as strychnine, was asserted.

The active agent has been estimated present at about 0.2-0.7 mg per beetle, males producing significantly more than females; each beetle is on the order of 5% by weight of the active agent, cantharidin. The agent is secreted orally by the beetle, and is exuded from its joints as a milky fluid. The potency of the insect species as a vesicant has been known since antiquity and the activity has been used in various ways. This has led to its small-scale commercial preparation and sale, in a powdered form known as cantharides (the Greek plural of singular cantharis), obtained from dried and ground beetles. The crushed powder is of yellow-brown to brown-olive color with iridescent reflections, is of disagreeable scent, and is bitter to taste. Cantharidin, the active agent, is a terpenoid, and is also produced by various other insect species, such as Epicauta immaculata.

Activities and uses

As toxins

In man and animals, the cantharidin intoxication/toxicosis caused by the active agent from L. vesicatoria (and other species of blister beetle that produce cantharidin), broadly speaking, involves cellular level "disrup[tion of] the integrity of endothelial cells," which "leads to tissue destruction"; at a molecular level, activity of cantharide preparations has been attributed, at least in part, to the ability of cantharidin to inhibit the enzyme phosphatase 2A. Depending on dose, its use can cause topical irritation and blistering, and when taken orally, blistering, ulceration, and bleeding of the mouth, gastrointestinal (GI) and urinary tracts, and genitalia (and an accompanying range of discomfort to severe pain at all these sites); these effects can escalate to erosion and bleeding of mucosa in each system, followed at times by severe GI hemorrhaging and acute tubular necrosis and glomerular destruction, resulting in GI and renal dysfunction, by organ failure, and deat h.

Clinical and postmortem examinationâ€"e.g., by endoscopy and autopsyâ€"reveal the destruction described, as do laboratory findings of hematuria, proteinuria, heme-positive stool, and other reflections of the underlying pathology. The active agent, cantharadin, has been identified in plasma and urine as well as gastric contents and tissue preparations, using such techniques as high performance liquid chromatography and gas chromatography, in both of the cases sometimes linked with mass spectrometry, one-dimensional or tandem (e.g., LC-MS-MS), with tandem methods being described as optimal.

Management of cantharidin poisoning is only supportive.

Animal cases

Poisoning by Spanish fly/cantharides is a significant veterinary issue. Ingestion of blister beetles in infested hay or forage causes serious cantharidin toxicosis in animals in the U.S., especially in horses but also in cattle (with Epicauta spp. being the more predominant source), where severity varies according to dose. Symptoms range from "mild depression or discomfort" from abdominal pain, through mucosal erosion and gastrointestinal (GI) hemorrhaging (e.g., of the upper GI), to "severe pain, shock, and death." Inadvertent animal poisoning from the beetles via other sources is also known: cattle in Africa have shown excitement, diarrhea, and nephritis as a result of drinking water contaminated by such insects.

Veterinary management of poisoning is through supportive care. Gwaltney-Brant and coworkers note that in veterinary cases, damage to the GI tract may require broad spectrum antimicrobial treatment, with aminoglycosides being avoided because of their nephrotoxicity complicating cantharidin-induced nephrosis. Schmitz and others note that in these cases, early evacuation of the GI tract (e.g., aided by charcoal or mineral oil) may be therapeutically useful, and that calcium and magnesium supplementation for prolonged periods "is almost always indicated," alongside administering fluids/diuretics to maintain normal pH and electrolytes, and analgesics to manage pain.

Human cases

Preparations from L. vesicatoria and its active agent have been implicated in both inadvertent and intentional poisonings. Froberg notes a 1954 manslaughter case where cantharidin was administered in a coconut-flavoured candy as an intended aphrodisiac, resulting in illness and eventual death of two women (agent identified postmortem), and in facial blistering and criminal conviction and imprisonment of the perpetrator.

Karras and coworkers reported on four cases of Spanish fly poisoning presenting in a U.S. emergency department, with complaints of "dysuria and dark urine," in a general argument for medical awareness of its continuing misuse as an experimental sexual stimulant. Of these patients, three reported abdominal pain and one, flank pain; two had occult rectal bleeding and the one female had vaginal bleeding; other presenting symptoms included hematuria and a first report, in two patients, of low-grade disseminated intravascular coagulation. Karras more generally notes that symptoms of poisoning include "burning of the mouth, dysphagia, nausea, hematemesis, gross hematuria, and dysuria," that acute tubular necrosis and glomerular destruction can result in renal dysfunction, and that erosion and hemorrhaging of the mucosa can be seen in the upper gastrointestinal tract (GI tract).

Clinical management of human cantharidin poisoning is likewise through supportive care.

Clinical and postmortem findings

Clinical presentations associated with cantharidin toxicosis were summarized at the opening of this section on use of this natural agent as a toxin, inadvertently or intentionally. In the cases of handling of L. vesicatoria preparations or its active agent, clinical manifestations include evidence of its characteristic blistering. Laboratory findings following ingestion include "hematuria, proteinuria, and heme-positive stool." In patients under treatment, endoscopic examination may reveal hemorrhaging of the GI tract; postmortem, such GI hemorrhaging has been assigned as cause of death.

Historically, to determine if a human death had taken place by the effects of Spanish fly, investigators performed vesicación tests, for instance, rubbing oil-treated internal organs of the deceased on the shaved skin of a rabbit to look for the blistering effect of the cantharides on that skin.

In medicine

The cantharides derived from L. vesicatoria are poisonous if taken internally in large doses. As discussed by Karras, "[w]hile most commonly available preparations of Spanish fly contain [the active agent] cantharidin in negligible amounts, if at all, [it is nevertheless] available illicitly in concentrations capable of causing severe toxicity. Even so, medical use dates back to descriptions from Hippocrates. For modern controlled-dose medical uses, see the main article on cantharidin.

External

Historically, it has been used externally as a rubifacient, counterirritant, and vesicant. With regard to the last of these, there is report of plasters being made from wings of the beetles, in order to raise blisters.

Internal

As it passes through the urinary tract, cantharides irritate the genitals, resulting in increased blood flow that can mimic the engorgement that occurs with sexual excitement, leading to their supposed aphrodisiac effects. One modern text notes that a male erection caused by use of such preparations is "pathological, painful and devoid of sexual pleasure."

Despite the danger and their toxicity, attempts have been made to use cantharides internally as a diuretic, as an abortifacient, and as a stimulant (since one of its effects was producing insomnia and nervous agitation).

Preparations containing the active agent have a history of use as a Chinese herbal medicine, and such preparations appear in descriptions of homeopathic remedies, where in a relevant medical text they are listed with "Homeopathic Remedies Lacking Proof of Efficacy" (with a case study of danger imposed on an infant).

Culinary uses

In Morocco and other parts of North Africa, spice blends known as ras el hanout sometimes included as a minor ingredient "green metallic beetles", inferred to be cantharides from L. vesicatoria, although sale of this in Moroccan spice markets was banned in the 1990s. Dawamesk, a spread or jam made in North Africa and containing hashish, almond paste, pistachio nuts, sugar, orange or tamarind peel, cloves, and other various spices, occasionally included cantharides.

Other uses

In ancient China, the beetles were mixed with human excrement, arsenic, and wolfsbane to make the world's first recorded stink bomb. In Santería, cantharides are used in incense.

Noteworthy cases

Simón Bolívar may have been accidentally poisoned by application of Spanish fly.

Arthur Kendrick Ford was convicted and given a multiyear prison sentence in 1954 for the unintended deaths of two women surreptitiously given candies laced with cantharidin, which were intended to act as an aphrodisiac.

References

Further reading

• "Cantharides", Encyclopædia Britannica, 9th ed., Vol. V, New York: Charles Scribner's Sons, 1878, pp. 31â€"32 .
• "Cantharides", Encyclopædia Britannica, 11th ed., Vol. V, Cambridge: Cambridge University Press, 1911, pp. 212â€"213 .
• Guala, Gerald, ed. (2015). "Geographic Information: Geographic Division". ITIS Report: Lytta vesicatoria (Linnaeus, 1758), Taxonomic Serial No.: 114404. Reston, VA, USA: U.S. Geological Survey, Integrated Taxonomic Information System (ITIS). Retrieved 20 December 2015. 
• BHL content highlight on V. vesicatoria.
• Krinsky, William L. (2009). "Beetles (Coleoptera)". In Mullen, Gary R.; Durden, Lance A. Medical and Veterinary Entomology (2nd ed.). London, ENG: Elsevier Academic Press. pp. 101â€"114, esp. 104â€"105. ISBN 0080919693. Retrieved 14 December 2015. 
• Gwaltney-Brant, Sharon M.; Dunayer, Eric & Youssef, Hany (2012). "Terrestrial Zootoxins [Coleoptera: Meloidae (Blister Beetles)]". In Gupta, Ramesh C. Veterinary Toxicology: Basic and Clinical Principles (2nd ed.). London, ENG: Elsevier Academic Press. pp. 975â€"978. ISBN 0123859263. Retrieved 14 December 2015. 
• Schmitz, David G. (2013). "Overview of Cantharidin Poisoning (Blister Beetle Poisoning)". In Aiello, Susan E.; Moses, Michael A. The Merck Veterinary Manual. Kenilworth, NJ, USA: Merck Sharp & Dohme. ISBN 0911910611. Retrieved 14 December 2015. 
• Froberg, Blake A. (2010). "Animals". In Holstege, Christopher P.; Neer, Thomas; Saathoff, Gregory B.; Furbee, R. Brent. Criminal Poisoning: Clinical and Forensic Perspectives. Burlington, MA, USA: Jones & Bartlett. pp. 39â€"48, esp. 41, 43, 45ff. ISBN 1449617573. Retrieved 16 December 2015.  [Note: the active agent appears variously as cantharidin, and "can tharadin" or "canthariadin" (sic.).]
• Dunbar, George (1840). "ΚÎ'ΝΘ: Κανθαρις". A New Greek and English, and English and Greek Lexicon, with an Appendix Explanatory of Scientific Terms, Etc. Part 1. Edinburgh, Scotland: MacLachlan, Stewart. p. 301. Retrieved 14 December 2015. 
• The Eds. of Encyclopædia Britannica (2015). "Blister beetle, insect". Encyclopædia Britannica (online). Chicago, IL, USA: Encyclopædia Britannica. Retrieved 14 December 2015. 
• Milsten, Richard (2000). The Sexual Male: Problems and Solutions. W. W. Norton & Company. ISBN 0-393-32127-4. 
• Reichl, Ruth, ed. (2004). The Gourmet Cookbook. Houghton Mifflin. ISBN 0-618-37408-6.  CS1 maint: Multiple names: authors list (link)