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CANTHARIDIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cantharidin is a lipid soluble irritant extract derived from the blister beetle (especially Cantharis vesicatoria) which lives in southern Europe. Cantharidin is also found in various Mylabris species, and Epicanta rittata presently in the US (Presto & Muecke, 1970).

Specific Substances

    1) Canthandic acid anhydride
    2) Hexahydro-3,7-dimethyl-4,7,epoxyisobenzofuran-1,
    3) 3,dione
    4) Spanish Fly
    5) CAS 56-25-7
    1.2.1) MOLECULAR FORMULA
    1) C10-H12-O4

Available Forms Sources

    A) FORMS
    1) Types of cantharidin preparations:
    1) Cantharidin in flexible collodion
    2) Cantharidis pulvis
    3) Emplastrum cantharidini in massa
    4) Liquor cantharidini
    5) Liquor Epispasticus
    2) Cantharidin is available as cantharidin collodion (cantharone), which contains 0.7% cantharidin in a film-forming vehicle containing acetone, ethocel, flexible collodion, ether (35%), and alcohol (11%) (HSDB , 1990).
    B) SOURCES
    1) NATURAL SOURCES - Representative beetle species include (Nickolls & Teare, 1954; (Ross, 1948; Nicholls et al, 1990):
    1) Alloxacis species
    2) Cantharis vesicatoria
    3) Eobia decolor
    4) Eobia kanack
    5) Meloidae Family
    6)
    a) Epicanta species
    b) Meloe species
    c) Henous species
    7) Mylabris cicorii
    8) Mylabris phalerata
    9) Oxacis species
    10) Oxycopsis species
    11) Thelyphassa lineata
    2) BLISTER BEETLES: Especially Cantharis vesicatoria, are a natural source of cantharidin. The ovaries, soft tissues, and blood of these beetles contain the greatest concentrations.
    a) The average concentration is 2.6 to 4.3%, but the South African beetle, Mylabridae, may contain as much as 11% (Till & Majmudar, 1981; Schmitz & Reagor, 1987).
    3) EPICAUTA BLISTER BEETLES: Include (Edwards et al, 1989; Ray et al, 1989; Beasley et al, 1983):
    Name% cantharidin
    Epicauta albida 
    Epicauta attrivittata 
    Epicauta callosa 
    Epicauta confertaMale: 2.48 Female: 0.77
    Epicauta ficta 
    Epicauta funebris 
    Epicauta immaculata 
    Epicauta lemniscata0.47
    Epicauta maculata 
    Epicauta murina 
    Epicauta occidentalisMale: 3.31 Female: 0.47
    Epicauta pardalis 
    Epicauta pennsylvanica1.23
    Epicauta pestifera 
    Epicauta sericans 
    Epicauta texema 
    Epicauta torsa 

    a) Cantharidin is found in the hemolymph, genitalia, and possibly other Epicauta beetle tissues (Schmitz & Reagor, 1987).
    C) USES
    1) HOMICIDAL AGENT: It has been used as a homicidal agent in South Africa (Till & Majmudar, 1981).
    2) HERBAL USES: Other herbalist uses included treatment for dropsy, pleurisy, pericarditis, kidney infections, kidney stones, stranguria, certain venereal diseases, and amenorrhea. It has a well-known, but undeserved reputation as an aphrodisiac known as "Spanish Fly" (Friesen et al, 1979). Cantharidin has been used in traditional Chinese medicine to treat fungal infections, warts, various dermatologic conditions and to induce abortion; it is believed also to have antitumor effects (Chen & Leung, 1995).
    3) POWDER: A brown powder found in the possession of a deceased 36-year-old black male contained 0.87% cantharidin (Hundt et al, 1990). The source of the powder may have been an herbal doctor.
    4) MODERN USES: Cantharidin has been used as a counter-irritant and vesicant, and for removal of benign epithelial growths such as warts and molluscum contagiosum. It is an experimental antitumor agent (HSDB , 1990).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Cantharidin is a lipid soluble extract derived from the blister beetle. There are more than 200 species of blister beetle worldwide. The most commonly implicated beetle is "Spanish Fly" (Cantharis vesicatoria); however, the highest concentration of cantharidin is found in the Chinese blister beetle (Mylabris cichorii L.). It has historically been utilized for its aphrodisiac properties and is known as "Spanish Fly." Cantharidin has also been utilized in Chinese medicine to treat fungal infections, warts, and various dermatologic conditions and to induce abortions. Currently, cantharidin is occasionally used by dermatologists to remove warts and molluscum contagiosum. It has also been studied as an experimental antitumor agent.
    B) PHARMACOLOGY: Cantharidin is a powerful vesicant and potent irritant. It is a volatile double-ringed structure that is crystalline, colorless, odorless, and water insoluble. It is secreted by adult male beetles near the leg joints in hemolymph. Females do not produce cantharidin but can extrude it as a result of copulation deposition.
    C) TOXICOLOGY: The irritant contact dermatitis results in intraepidermal and subepidermal blistering, epidermal necrosis, and acantholysis. It is caused by activation of neutral proteases that destroy dense desmosomal plaques. Cantharidin is also a potent inhibitor of protein phosphatases 1 and 2A. This results in the detachment of tonofilaments from desmosomes and the appearance of intraepidermal blisters. Biopsies reveal intraepidermal vesicles with fibrin, polymorphonuclear cells, and acanthocytes. Large ingestions may produce acute renal tubular necrosis with loss of brush borders, cloudy swelling, and hydropic degeneration resulting in renal injury and hematuria. Because cantharidin is a powerful vesicant and irritant, oral and ophthalmic exposures can result in vesiculobullous lesions, mucosal edema, and keratoconjunctivitis.
    D) EPIDEMIOLOGY: Cantharidin exposure/ingestions are rare poisonings that very rarely result in serious morbidity or death.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects include irritant dermatitis, dermal vesicles and bullae, conjunctivitis, priapism, and hematuria.
    2) RARE: Other more rare adverse effects include renal failure, liver injury, gastrointestinal hemorrhage, coagulopathy, airway obstruction, seizure, dysrhythmias, and shock.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild inflammation of the dermis, oral or genital mucosa, and conjunctiva, fever, nausea, vomiting, wheeze, and lymphadenopathy.
    2) SEVERE TOXICITY: Severe mucosal, dermal, or conjunctival injury, renal failure, liver injury, gastrointestinal hemorrhage, coagulopathy, airway obstruction, seizure, dysrhythmias, and shock.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hypotension may develop with severe poisonings. Heart rate and respiration may be initially stimulated and then depressed.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Conjunctivitis, keratitis, iritis, and edema of the lids have been noted.
    2) A burning sensation of the mouth and throat after ingestion is common.
    3) Swelling and blistering of the tongue can develop.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Tachycardia may occur. Hypotension, ST elevation and T-wave abnormalities have been reported after severe poisoning.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Edema and subpleural hemorrhage may be seen but rarely produce significant damage.
    a) Respirations may be briefly stimulated and then greatly depressed.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Neurologic effects include delirium, syncope, ataxia, coma, and occasionally seizures and flaccid paralysis.
    0.2.8) GASTROINTESTINAL
    A) ANIMAL STUDIES: In animal studies, extensive epithelial cell damage to the esophagus, stomach, and small and large intestine was noted.
    B) WITH POISONING/EXPOSURE
    1) Ingestion may lead to desquamation and loss of the normal mucosal surfaces from the tongue to the pylorus. There may be hemorrhage or blisters. Vomiting, tenesmus, diarrhea, dysphagia, abdominal pain, and necrosis of the gastrointestinal mucosa may be seen.
    0.2.9) HEPATIC
    A) WITH POISONING/EXPOSURE
    1) Fatty changes and parenchymatous degeneration may be seen in severe cases.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) Polyuria, proteinuria, and gross or microscopic hematuria may be seen. Flank pain, dysuria, urinary frequency, urgency and hesitancy are also common after ingestion. Priapism and uterine bleeding may also occur.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH POISONING/EXPOSURE
    1) There may be severe vomiting and diarrhea, which can lead to fluid and electrolyte depletion.
    0.2.13) HEMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Anemia may develop secondary to blood loss. Mild coagulation abnormalities and thrombocytopenia have been reported. Leukocytosis is common with significant poisoning. Hemoconcentration may occur secondary to vomiting and diarrhea.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Mild to severe reactions may be seen. Cantharidin is a vesicant and may cause blisters within 4 to 5 hours of application. Acantholysis may be seen. Cantharidin has been used in vivo to induce acantholysis.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no studies were found on the possible reproductive effects of cantharidin in humans or experimental animals.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the potential carcinogenicity of cantharidin in humans.

Laboratory Monitoring

    A) Laboratory studies are generally unnecessary since cantharidin overdose/exposed patients manifest mild symptoms and signs.
    B) With massive/significant ingestions, monitor serum electrolytes, CBC, coagulation studies, renal function, liver enzymes, venous or arterial blood gas, and urinalysis.
    C) Consider checking acetaminophen and salicylate concentrations if there is any uncertainty of drug ingested.
    D) Cantharidin levels are not rapidly available or helpful in the acute setting.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Symptomatic and supportive care are usually sufficient for the treatment of mild to moderate toxicity. Wash exposed areas with soap and water. Treat pain with appropriate analgesia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is primarily symptomatic and supportive with careful attention to airway if the patient becomes obtunded or if there is profound airway swelling. Treat hypotension with IV fluids and pressors if needed. Treat seizures with benzodiazepines. Transfusion may be necessary if the patient develops severe gastrointestinal hemorrhage. Endoscopy should also be performed in patients with dysphagia, abdominal pain, severe oral burns or gastrointestinal hemorrhage.
    C) DECONTAMINATION
    1) PREHOSPITAL: Oral exposures can be diluted with water or milk if there are no signs of airway obstruction. Do not administer activated charcoal as it is unlikely to affect tissue injury and activated charcoal may obscure endoscopy.
    2) HOSPITAL: Avoid activated charcoal after ingestion as it is unlikely to affect tissue injury and may obscure endoscopy.
    D) AIRWAY MANAGEMENT
    1) Administer 100% oxygen as needed for respiratory support. Intubate and provide assisted ventilation as necessary for respiratory distress or airway edema.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Cantharidin is not effectively eliminated by hemodialysis, but dialysis may be necessary if renal failure develops.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patient may be observed at home for small exposures/unintentional ingestions with mild symptoms.
    2) OBSERVATION CRITERIA: Any patient who manifests signs of toxicity (ie, mild inflammation of the dermis, oral or genital mucosa, and conjunctiva, fever, nausea, vomiting, or wheeze) after ingestion or exposure should be sent to a healthcare facility for observation. Patients with large dermal exposures should also be sent in for evaluation. If symptoms resolve in the emergency department and the home social situation permits, the patient may be discharged after psychiatric clearance if needed.
    3) ADMISSION CRITERIA: Patients who present with severe symptoms should be admitted. In addition, if the above mild findings persist despite treatment in the emergency department, admit the patient to the appropriate level of care.
    4) CONSULT CRITERIA: Consult a medical toxicologist, burn surgeon, gastroenterologist, or nephrologist as needed, especially for patients admitted to the ICU.
    H) PITFALLS
    1) Failure to recognize that dermal symptoms can be delayed up to 96 hours with some species and that ingestion can cause airway compromise and gastrointestinal hemorrhage.
    I) TOXICOKINETICS
    1) Vesiculation can be delayed from 12 to 96 hours after exposure to Paederus species (whiplash rove beetles) compared to 2 to 3 hours after exposure to cantharidin from Meloidae and Oedemeridae families. If absorbed orally, onset of action can be rapid or delayed (ie, 10 minutes to a few hours).
    J) PREDISPOSING CONDITIONS
    1) Atopy, chronic kidney disease, and reactive airway disease predispose patients to toxicity.
    K) DIFFERENTIAL DIAGNOSIS
    1) Irritant or allergic contact dermatitis, thermal or chemical burns, pemphigus, dermatitis herpetiformis, herpes simplex, herpes zoster, impetigo, and porphyria.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Wash exposed areas with soap and water and remove contaminated clothing.

Range Of Toxicity

    A) TOXICITY: The range noted for minimal lethal dose of cantharidin is 32 to 65 mg. As little as 10 mg has been reported to be fatal; however, exposure to 175 mg resulted in severe toxicity, but the patient survived. As few as 4 to 24 dried blister beetles may produce serious or fatal ingestion. A fatality was noted when a patient ingested extract from 200 Mylabris phalerata beetles to induce abortion.
    B) THERAPEUTIC DOSE: For treatment of warts, 0.7% liquid is applied over the surface of the wart with repeat dose in 2 to 3 weeks.

Clinical Effects

Summary Of Exposure

    A) USES: Cantharidin is a lipid soluble extract derived from the blister beetle. There are more than 200 species of blister beetle worldwide. The most commonly implicated beetle is "Spanish Fly" (Cantharis vesicatoria); however, the highest concentration of cantharidin is found in the Chinese blister beetle (Mylabris cichorii L.). It has historically been utilized for its aphrodisiac properties and is known as "Spanish Fly." Cantharidin has also been utilized in Chinese medicine to treat fungal infections, warts, and various dermatologic conditions and to induce abortions. Currently, cantharidin is occasionally used by dermatologists to remove warts and molluscum contagiosum. It has also been studied as an experimental antitumor agent.
    B) PHARMACOLOGY: Cantharidin is a powerful vesicant and potent irritant. It is a volatile double-ringed structure that is crystalline, colorless, odorless, and water insoluble. It is secreted by adult male beetles near the leg joints in hemolymph. Females do not produce cantharidin but can extrude it as a result of copulation deposition.
    C) TOXICOLOGY: The irritant contact dermatitis results in intraepidermal and subepidermal blistering, epidermal necrosis, and acantholysis. It is caused by activation of neutral proteases that destroy dense desmosomal plaques. Cantharidin is also a potent inhibitor of protein phosphatases 1 and 2A. This results in the detachment of tonofilaments from desmosomes and the appearance of intraepidermal blisters. Biopsies reveal intraepidermal vesicles with fibrin, polymorphonuclear cells, and acanthocytes. Large ingestions may produce acute renal tubular necrosis with loss of brush borders, cloudy swelling, and hydropic degeneration resulting in renal injury and hematuria. Because cantharidin is a powerful vesicant and irritant, oral and ophthalmic exposures can result in vesiculobullous lesions, mucosal edema, and keratoconjunctivitis.
    D) EPIDEMIOLOGY: Cantharidin exposure/ingestions are rare poisonings that very rarely result in serious morbidity or death.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects include irritant dermatitis, dermal vesicles and bullae, conjunctivitis, priapism, and hematuria.
    2) RARE: Other more rare adverse effects include renal failure, liver injury, gastrointestinal hemorrhage, coagulopathy, airway obstruction, seizure, dysrhythmias, and shock.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild inflammation of the dermis, oral or genital mucosa, and conjunctiva, fever, nausea, vomiting, wheeze, and lymphadenopathy.
    2) SEVERE TOXICITY: Severe mucosal, dermal, or conjunctival injury, renal failure, liver injury, gastrointestinal hemorrhage, coagulopathy, airway obstruction, seizure, dysrhythmias, and shock.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypotension may develop with severe poisonings. Heart rate and respiration may be initially stimulated and then depressed.
    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Respirations may be briefly stimulated and then greatly depressed (HSDB , 1992).
    3.3.4) BLOOD PRESSURE
    A) HYPOTENSION
    1) WITH POISONING/EXPOSURE
    a) Shock has been reported with cantharidin poisoning (Chen & Leung, 1995).
    b) CASE REPORT: Hypotension was reported in a 19-year-old who had ingested an unknown quantity 14 hours previously. She also exhibited symptoms of shock and CNS depression (Craven & Polak, 1954).
    c) CASE REPORT: Hypotension was also reported following a 175 mg ingestion (Oaks et al, 1960).
    d) A 36-year-old man drank the liquid of fried Cantharides beetles and developed massive gastrointestinal bleeding, desquamation of the oral mucosa, hematuria, acute renal failure and shock. Hemodynamic compromise developed 40 minutes after ingestion. He died of multiorgan failure 32 hours after ingestion (Chen & Leung, 1995).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Heart rate may be briefly stimulated and then depressed (HSDB , 1992).

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Conjunctivitis, keratitis, iritis, and edema of the lids have been noted.
    2) A burning sensation of the mouth and throat after ingestion is common.
    3) Swelling and blistering of the tongue can develop.
    3.4.3) EYES
    A) CONJUNCTIVITIS
    1) WITH POISONING/EXPOSURE
    a) Keratitis, iritis, and edema of the lids have been noted in human studies (Grant & Schuman, 1993).
    2) ANIMAL STUDIES
    a) Keratitis, iritis, and edema of the lids have been noted in animal studies (Grant & Schuman, 1993).
    b) CANTHARONE LIQUID: This wart preparation contains 0.7% cantharidin in a vehicle of acetone and collodion. When tested on the corneas of rabbits it was irritating, but it did not produce permanent stromal changes (Grant & Schuman, 1993).
    3.4.6) THROAT
    A) IRRITATION
    1) WITH POISONING/EXPOSURE
    a) A burning sensation of the mouth and throat, and swelling and blistering of the tongue can develop after ingestion (Craven & Polak, 1954; Cheng et al, 1990; EPA, 1985; HSDB , 1991).
    2) ANIMAL STUDIES: Signs suggestive of oral irritation have been noted in horses after ingestion of alfalfa hay or products contaminated with "blister" beetles (Schmitz, 1989).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachycardia may occur. Hypotension, ST elevation and T-wave abnormalities have been reported after severe poisoning.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) The most common cardiac abnormalities are ventricular ectopic beats, ventricular tachycardia, and ventricular fibrillation (Till & Majmudar, 1981; Rabkin et al, 1979).
    b) ST elevations, transient T wave inversions, and T wave amplitude changes have been noted in humans (Oaks et al, 1960; Friesen et al, 1979).
    B) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Sinus tachycardia with normal blood pressure has been observed (Ewart et al, 1978). Heart rate may be briefly stimulated and then become greatly depressed (HSDB , 1992).
    C) HEMOPERICARDIUM
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: One early case demonstrated multiple hemorrhages in the pericardium and a subendocardial hemorrhage in the interventricular septum (Nickolls & Teare, 1954).
    D) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Hypotension was reported in a 19-year-old who had ingested an unknown quantity 14 hours previously. She also exhibited symptoms of shock and CNS depression at this time (Craven & Polak, 1954).
    b) CASE REPORT: A second patient involving a 175 mg ingestion also resulted in hypotension (Oaks et al, 1975).
    c) CASE REPORT: A 36-year-old man drank the liquid of fried Cantharides beetles and developed massive gastrointestinal bleeding, desquamation of the oral mucosa, hematuria, acute renal failure and shock. Hemodynamic compromise developed 40 minutes after ingestion. He died of multiorgan failure 32 hours after ingestion (Chen & Leung, 1995).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DYSRHYTHMIA
    a) RABBITS: Dose-related effects observed following bolus injection of cantharidin in rabbits included presence, magnitude and duration of ST depression after injection; occurrence of fatal dysrhythmias; survival time; and electron microscopic evidence of mitochondrial swelling, intramitochondrial granules, and myofibrillar degeneration (Rabkin et al, 1979).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Edema and subpleural hemorrhage may be seen but rarely produce significant damage.
    a) Respirations may be briefly stimulated and then greatly depressed.
    3.6.2) CLINICAL EFFECTS
    A) HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) Although edema and subpleural hemorrhages may be seen, the lungs are usually not seriously damaged (Till & Majmudar, 1981).
    B) HYPERVENTILATION
    1) WITH POISONING/EXPOSURE
    a) Respirations may be briefly stimulated and then greatly depressed (HSDB , 1992).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Neurologic effects include delirium, syncope, ataxia, coma, and occasionally seizures and flaccid paralysis.
    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 19-year-old woman developed shock and coma approximately 14 hours postingestion (Craven & Polak, 1954).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures occur in rare circumstances (Oaks et al, 1960).
    C) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Ataxia has been reported in a 5-year-old after topical application (Till & Majmudar, 1981).
    D) FLACCID PARALYSIS
    1) WITH POISONING/EXPOSURE
    a) A Guillain-Barre type of flaccid paralysis has been reported with cantharidin poisoning; spontaneous reversal occurred in both cases (Harrisberg et al, 1984).

Gastrointestinal

    3.8.1) SUMMARY
    A) ANIMAL STUDIES: In animal studies, extensive epithelial cell damage to the esophagus, stomach, and small and large intestine was noted.
    B) WITH POISONING/EXPOSURE
    1) Ingestion may lead to desquamation and loss of the normal mucosal surfaces from the tongue to the pylorus. There may be hemorrhage or blisters. Vomiting, tenesmus, diarrhea, dysphagia, abdominal pain, and necrosis of the gastrointestinal mucosa may be seen.
    3.8.2) CLINICAL EFFECTS
    A) ULCERATIVE STOMATITIS
    1) WITH POISONING/EXPOSURE
    a) Ingestion may lead to desquamation or to a total loss of normal mucosal surfaces from the tongue to the pylorus. The mouth may initially be erythematous and edematous and later show patches of ulceration. There may be hemorrhage (Chen & Leung, 1995; Till & Majmudar, 1981) or blisters (Craven & Polak, 1954).
    1) Necrosis of esophageal and gastric mucosa may occur (HSDB , 1992). One patient with fatal cantharidin poisoning developed pneumomediastinum, possibly secondary to esophageal perforation (Chen & Leung, 1995).
    B) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Vomiting and/or hematemesis may develop (Mallari et al, 1996; Karras et al, 1996). Petechial hemorrhage and mucosal erosion may be seen in the stomach (Till & Majmudar, 1981; Cheng et al, 1990; Presto & Muecke, 1970; EPA, 1985). In severe poisoning life-threatening gastrointestinal bleeding may occur (Chen & Leung, 1995).
    b) DOSE RESPONSE EFFECT: GI symptoms are dependent on the dose and the amount of lipids in the GI tract (Till & Majmudar, 1981).
    C) TENESMUS
    1) WITH POISONING/EXPOSURE
    a) Tenesmus is a prominent symptom (Till & Majmudar, 1981; HSDB , 1991).
    D) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea has been observed following exposure (Craven & Polak, 1954).
    E) DYSPHAGIA
    1) WITH POISONING/EXPOSURE
    a) Dysphagia may occur after ingestion (Oaks et al, 1960).
    F) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal pain may develop after ingestion (Mallari et al, 1996; Oaks et al, 1960; Cheng et al, 1990).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) GASTROINTESTINAL DISORDER
    a) RATS: Extensive epithelial cell damage to the esophagus, stomach, small and large intestines was found following cantharidin injection in rats (Bagatell et al, 1969).

Hepatic

    3.9.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Fatty changes and parenchymatous degeneration may be seen in severe cases.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH POISONING/EXPOSURE
    a) The cytoplasm of hepatocytes was reported as swollen and granular, with indistinct cell borders. Various nuclear alterations may be seen, including binucleation, pyknosis, karyorrhexis, and karyolysis.
    1) There is little evidence of inflammatory response (Oaks et al, 1960; Opie, 1912; Bagatell et al, 1969).
    B) STEATOSIS OF LIVER
    1) WITH POISONING/EXPOSURE
    a) Fatty changes of the liver were seen in one case 24 hours after ingestion (Nickolls & Teare, 1954).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) RATS - Cantharidin had a severe effect on hepatic and other organ structure, but no effect on cholesterol or phospholipids following intraperitoneal injection of rats (Bagatell et al, 1969).

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Polyuria, proteinuria, and gross or microscopic hematuria may be seen. Flank pain, dysuria, urinary frequency, urgency and hesitancy are also common after ingestion. Priapism and uterine bleeding may also occur.
    3.10.2) CLINICAL EFFECTS
    A) POLYURIA
    1) WITH POISONING/EXPOSURE
    a) Polyuria and mild dysuria may occur shortly after cantharidin poisoning. Cases have been reported when a patient may change from being polyuric to oliguric within a few hours (Till & Majmudar, 1981; Craven & Polak, 1954; HSDB , 1991).
    B) DYSURIA
    1) WITH POISONING/EXPOSURE
    a) Burning pain in the bladder and urethra and strangury may develop (HSDB , 2001). Flank pain, dysuria , urinary frequency, urgency and hesitancy may develop secondary to local irritation of the genitourinary tract after ingestion (Karras et al, 1996).
    C) RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Acute oliguric renal failure was noted in a fatality who ingested an "elixir" from 200 beetles (Cheng et al, 1990). Acute renal failure has been reported after ingestion in several cases (Chen & Leung, 1995; Tagwireyi et al, 2000; Fisch et al, 1978; Harrisberg et al, 1984).
    b) CASE SERIES: Renal biopsy performed in 2 cases of cantharidin intoxication and renal failure resulted in only minimal changes (ie, podocyte swelling of glomeruli). The tubuli were markedly changed with intraluminal cell debris, luminal enlargement, flattening and shrinking of the epithelial cells, and distortion of brush borders (Fisch et al, 1978).
    D) BLOOD IN URINE
    1) WITH POISONING/EXPOSURE
    a) Gross and microscopic hematuria are common after significant ingestion (Mallari et al, 1996; Tagwireyi et al, 2000; Karras et al, 1996; Chen & Leung, 1995). On autopsy, blood has been seen in the renal pelvises, ureters, and bladder. Kidneys can be engorged with blood (Till & Majmudar, 1981).
    E) ALBUMINURIA
    1) WITH POISONING/EXPOSURE
    a) Proteinuria often develops in patients with hematuria (Karras et al, 1996; Tagwireyi et al, 2000; Mallari et al, 1996).
    F) NEPHRITIS
    1) WITH POISONING/EXPOSURE
    a) The lesions caused by cantharidin are generally classified as vascular nephritis, but there also appears to be widespread epithelial damage (Pearce, 1913).
    G) PRIAPISM
    1) WITH POISONING/EXPOSURE
    a) When used as an aphrodisiac, it may cause priapism (Till & Majmudar, 1981).
    H) HEMATOMETRA
    1) WITH POISONING/EXPOSURE
    a) Uterine bleeding and pelvic edema occasionally occur in females when this agent is used as an aphrodisiac (Karras et al, 1996; Till & Majmudar, 1981).
    I) TERMINATION OF PREGNANCY
    1) WITH POISONING/EXPOSURE
    a) Cantharidin has been used in an attempt to induce abortion, sometimes with fatal outcome (HSDB , 2001).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) UROGENITAL MALFORMATION
    a) RATS - Extensive epithelial cell damage to the bladder and ureter was found following cantharidin injection in rats (Bagatell et al, 1969).

Hematologic

    3.13.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Anemia may develop secondary to blood loss. Mild coagulation abnormalities and thrombocytopenia have been reported. Leukocytosis is common with significant poisoning. Hemoconcentration may occur secondary to vomiting and diarrhea.
    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH POISONING/EXPOSURE
    a) Anemia may develop secondary to blood loss from the gastrointestinal and/or genitourinary tracts (Karras et al, 1996).
    B) BLOOD COAGULATION DISORDER
    1) WITH POISONING/EXPOSURE
    a) Mild coagulopathies (slightly prolonged INR/PT, PTT, depressed fibrinogen and the presence of fibrin split products) were reported in 4 patients who ingested cantharidin as an aphrodisiac (Karras et al, 1996). One of these patients also developed mild thrombocytopenia.
    C) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) Leukocytosis is common (Karras et al, 1996; Mallari et al, 1996).
    D) ERYTHROCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) Pseudopolycythemia may be seen secondary to hemoconcentration caused by dehydration (Oaks et al, 1960; Lipsitz et al, 1917; Harrisberg et al, 1984).
    E) LACK OF EFFECT
    1) WITH POISONING/EXPOSURE
    a) BONE MARROW ABNORMALITIES: None have been observed with this agent (Oaks et al, 1960).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA HYPOCHROMIC
    a) DOGS given cantharides showed a decrease in hemoglobin, but no significant change in red blood cells (Nyazema et al, 1991).
    2) LEUKOCYTOSIS
    a) DOGS: White blood cells increased after a dose of cantharides in dogs, reaching a peak at 6 hours (Nyazema et al, 1991).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Mild to severe reactions may be seen. Cantharidin is a vesicant and may cause blisters within 4 to 5 hours of application. Acantholysis may be seen. Cantharidin has been used in vivo to induce acantholysis.
    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Mild to severe reactions may be seen. A mild reaction to dermal application would include erythema and inflammation (Till & Majmudar, 1981).
    B) BULLOUS ERUPTION
    1) WITH POISONING/EXPOSURE
    a) Cantharidin is a vesicant and may cause blisters within 4 to 5 hours of application. Symptoms after dermal exposure may range anywhere from the mild inflammation mentioned above through severe blistering, ulceration, and necrosis (Till & Majmudar, 1981; Cheng et al, 1990).
    b) Beetle-caused lesions may be solitary or in groups of 2 or 3. The vesicles or bullae may be 2 to 30 mm wide and contain clear fluid with little erythema. There may be linear or "whiplash" lesions seen (Nicholls et al, 1990).
    c) Bullous lesions develop when cantharidin is released from the body of 3 major groups of beetles at the time the insect is crushed or rubbed on exposed skin (Mendez et al, 1989; Nicholls et al, 1990).
    C) DISORDER OF SKIN
    1) WITH POISONING/EXPOSURE
    a) ACANTHOLYSIS has been reported (Stoughton & Bagatell, 1959; Weakley & Einbinder, 1962).
    1) Cantharidin has been used in vivo to induce acantholysis (Pierard-Franchimont & Pierard, 1988). The primary detectable cellular event in cantharide acantholysis is the dissolution of dense plaque which leads to the detachment of tonofilaments from desmosomes (Bertaux et al, 1988).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no studies were found on the possible reproductive effects of cantharidin in humans or experimental animals.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) ABORTION
    1) Various cantharidin-containing preparations have been used to induce abortion (Cheng et al, 1990).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS56-25-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Cantharidin
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the potential carcinogenicity of cantharidin in humans.
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) MICE - In mice, cantharidin was found to be an equivocal tumorigenic agent and neoplastic by RTECS criteria with skin and appendage tumors (RTECS , 1991). Cantharidin acted as a weak but complete carcinogen in mice following topical application; however, carcinomas did not appear before about 16 months of observation (Laerum & Iversen, 1972).
    2) MICE - Repeated application of cantharidin to the skin of mice caused an increased incidence of reticulum cell tumors or malignant lymphomas and skin papillomas, compared with controls and acted as a tumor promoter. It also promoted skin papilloma formation in mice painted with dimethylbenzathracene (IARC, 1974).

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Laboratory studies are generally unnecessary since cantharidin overdose/exposed patients manifest mild symptoms and signs.
    B) With massive/significant ingestions, monitor serum electrolytes, CBC, coagulation studies, renal function, liver enzymes, venous or arterial blood gas, and urinalysis.
    C) Consider checking acetaminophen and salicylate concentrations if there is any uncertainty of drug ingested.
    D) Cantharidin levels are not rapidly available or helpful in the acute setting.

Methods

    A) CHROMATOGRAPHY
    1) Cantharidin may be isolated in blood, urine, or beetles using gas chromatography-mass spectrometric methods (Steyn & Hundt, 1988; Cheng et al, 1990).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who present with severe symptoms should be admitted. In addition, if mild findings (ie, mild inflammation of the dermis, oral or genital mucosa, and conjunctiva, fever, nausea, vomiting, or wheeze) persist despite treatment in the emergency department, admit the patient to the appropriate level of care.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patient may be observed at home for small exposures/unintentional ingestions with mild symptoms.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist, burn surgeon, gastroenterologist, or nephrologist as needed, especially for patients admitted to the ICU.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient who manifests signs of toxicity (ie, mild inflammation of the dermis, oral or genital mucosa, and conjunctiva, fever, nausea, vomiting, or wheeze) after ingestion or exposure should be sent to a healthcare facility for observation. Patients with large dermal exposures should also be sent in for evaluation. If symptoms resolve in the emergency department and the home social situation permits, the patient may be discharged after psychiatric clearance if needed.

Monitoring

    A) Laboratory studies are generally unnecessary since cantharidin overdose/exposed patients manifest mild symptoms and signs.
    B) With massive/significant ingestions, monitor serum electrolytes, CBC, coagulation studies, renal function, liver enzymes, venous or arterial blood gas, and urinalysis.
    C) Consider checking acetaminophen and salicylate concentrations if there is any uncertainty of drug ingested.
    D) Cantharidin levels are not rapidly available or helpful in the acute setting.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Do not administer activated charcoal as it is unlikely to affect tissue injury, and activated charcoal may obscure endoscopy.
    B) Oral exposures can be diluted with water or milk if there are no signs of airway obstruction.
    C) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    6.5.2) PREVENTION OF ABSORPTION
    A) Avoid activated charcoal after ingestion as it is unlikely to affect tissue injury, and activated charcoal may obscure endoscopy.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Laboratory studies are generally unnecessary since cantharidin overdose/exposed patients manifest mild symptoms and signs.
    2) With massive/significant ingestions, monitor serum electrolytes, CBC, coagulation studies, renal function, liver enzymes, venous or arterial blood gas, and urinalysis.
    3) Consider checking acetaminophen and salicylate concentrations if there is any uncertainty of drug ingested.
    4) Cantharidin levels are not rapidly available or helpful in the acute setting.
    B) ANALGESIC
    1) Narcotics are sometimes recommended for the relief of pain.
    C) ANTIEMETIC
    1) Are sometimes required due to extensive vomiting.
    D) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Administer intravenous fluids in patients with significant vomiting and/or diarrhea, hematuria or gastrointestinal bleeding.
    E) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    F) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    G) ENDOSCOPIC PROCEDURE
    1) Endoscopy of the upper gastrointestinal tract should be performed on patients with dysphagia, persistent abdominal pain, gastrointestinal bleeding, or severe oral burns after ingestion, to evaluate the severity of injury to the gastrointestinal mucosa.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) The skin should be thoroughly decontaminated since absorption via the lipid layers of the skin may cause systemic toxicity. Consider cleansing skin with acetone, ether, fatty soap, or alcohol, since these substances dissolve or dilute the cantharidin (Burnett et al, 1987).
    6.9.2) TREATMENT
    A) SUPPORT
    1) Application of steroid cream to skin blebs may be helpful. Lesions usually subside in 2 to 3 days. Consult with a burn center for large exposures.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) In those cases where renal failure occurs, hemodialysis may be necessary. There is no evidence that cantharidin is removed by hemodialysis.
    B) DIURESIS
    1) Maintenance of high urine flow (2 to 3 milliliters/kilogram/hour) should be of benefit since the toxin apparently is a direct irritant to renal and bladder mucosae. This may be achieved with aggressive use of intravenous fluids in most patients.
    2) If diuretics are needed, mannitol may be preferable to furosemide as the benefits of dilution will thus be afforded the proximal as well as distal tubule (Personal Communication, 1978).

Abstracts

Case Reports

    A) ROUTE OF EXPOSURE
    1) ORAL: A 43-year-old man created a solution of cantharidin 65 mg dissolved in water and was using this mixture to soak fish bait to make it more "sexy". After getting some of the mixture on his thumb from shaking the bottle, the patient pricked his thumb on a hook and sucked his thumb. He died shortly thereafter (Nickolls & Teare, 1954).
    2) ORAL: Five cases of cantharidin intoxication were reported following use as an aphrodisiac or to induce abortion. All patients presented with urinary tract symptoms, 4 had gross hematuria, and 1 had non-oliguric renal failure. Although all of these patients recovered completely, deaths have been associated with cantharidin poisoning (Fisch et al, 1978).
    3) DERMAL: A 1908 case involved cantharidin liquor (1:2 dilution) being painted on an area of a patient's abdomen near the base of the lung. The area painted was approximately 7 X 2.75 inches. After one hour there were signs of urgency, hematuria, tachycardia, profuse sweating, pain at the distal end of the penis, and dysuria, followed by at least two days of oliguria. The patient eventually recovered completely (Avery, 1908).

Range Of Toxicity

Summary

    A) TOXICITY: The range noted for minimal lethal dose of cantharidin is 32 to 65 mg. As little as 10 mg has been reported to be fatal; however, exposure to 175 mg resulted in severe toxicity, but the patient survived. As few as 4 to 24 dried blister beetles may produce serious or fatal ingestion. A fatality was noted when a patient ingested extract from 200 Mylabris phalerata beetles to induce abortion.
    B) THERAPEUTIC DOSE: For treatment of warts, 0.7% liquid is applied over the surface of the wart with repeat dose in 2 to 3 weeks.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Cantharidin was withdrawn from the United States' market by the U.S. Food and Drug Administration in 1992. However, in December 1998, cantharidin (for topical use in professional office setting only) was placed on the FDA's proposed list of bulk drug substances that may be used in pharmacy compounding and it is available as a powder in the United States.
    7.2.2) PEDIATRIC
    A) GENERAL
    1) Cantharidin was withdrawn from the United States' market by the U.S. Food and Drug Administration in 1992. However, in December 1998, cantharidin (for topical use in professional office setting only) was placed on the FDA's proposed list of bulk drug substances that may be used in pharmacy compounding and it is available as a powder in the United States.
    B) VERRUCA PLANTARIS (PLANTAR WARTS)
    1) PLANTAR WARTS were successfully treated in 81 of 121 children utilizing a combination of Cantharidin 1%, salicylic acid 30%, and podophyllin 5% . Patients from 2 to 16 years-of-age were treated for solitary or 2 plantar warts at a time, all patients or their families were contacted up to 6 months to a year after treatment to determine if the warts had recurred. All patients in the series adhered to the following protocol: 1) warts were debrided prior application of the topical solution, 2) application of CANTHARIDIN 1% containing solution, 3) occlusion of the area with a Band-Aid or gauze dressing which was left in place for 24 hours, 4) after 24 hours the dressing was removed and the medication washed off, 5) the patient was advised to soak the foot daily in warm water, and 6) a dressing was recommended when the foot was not soaking. All patients were seen 7 days after application in order to debride and apply silver nitrate to the base of the debrided tissue. Treatment was effective in 77 patients after one application, 1 patient received 2 treatments, 3 patients required 3 applications, and 19 failed to respond (Coskey, 1984)

Minimum Lethal Exposure

    A) ACUTE
    1) Although the minimum lethal exposure has not been well documented in the literature, as little as 10 milligrams has reportedly resulted in death (Melen, 1922), the usual "minimal lethal dose" quoted is between 32 to 65 milligrams (Cheng et al, 1990; Nickolls & Teare, 1954).
    2) Ingestion of the crude extract from over 200 Mylabris phalerata beetles for abortion resulted in a fatality (Cheng et al, 1990).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) Up to 50 milligrams has been tolerated (Melen, 1922).
    2) Exposure to 175 milligrams caused second and third degree burns of the mouth, seizures, kidney damage, and hypotension, but the patient survived (Oaks et al, 1960).
    3) Ewart et al (1978) reported a case where 105 to 140 milligrams was ingested. The oral mucosa became inflamed and ulcerated; the patient developed hematuria, and T wave abnormalities, but recovered.
    4) As little as 0.5 milligram lodged in the mucosa will produce a blister and possible systemic effects, and as little as 32 to 65 milligrams may be fatal (Nickolls & Teare, 1954).
    5) As few as 4 to 24 dried blister beetles may produce a serious or fatal ingestion (Cheng et al, 1990).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) No toxic serum and blood concentration has been established.
    2) CASE REPORTS
    a) In one fatal case, the antemortem and postmortem blood levels were 0.27 and 0.11 microgram per milliliter (Cheng et al, 1990).
    b) Another fatality thought due to cantharidin had a postmortem blood level of 0.072 microgram per milliliter (Steyn & Hundt, 1988).

Workplace Standards

    A) ACGIH TLV Values for CAS56-25-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS56-25-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS56-25-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Cantharidin
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS56-25-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 1 mg/kg (RTECS, 2004)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Cantharidin is a powerful vesicant and potent irritant. It is a volatile double-ringed structure that is crystalline, colorless, odorless, and water insoluble. It is secreted by adult male beetles near leg joints in hemolymph. Females do not produce cantharidin, but can extrude it as a result of copulation deposition (Barceloux, 2008).

Toxicologic Mechanism

    A) The irritant contact dermatitis results in intra-epidermal and sub-epidermal blistering, epidermal necrosis, and acantholysis. It is caused by activation of neutral proteases that destroy dense desmosomal plaques. Cantharidin is also a potent inhibitor of protein phosphatases 1 and 2A. This results in the detachment of tonofilaments from desmosomes and the appearance of intra-epidermal blisters. Biopsies reveal intra-epidermal vesicles with fibrin, polymorphonuclear cells, and acanthocytes. Large ingestions may produce acute renal tubular necrosis with loss of brush borders, cloudy swelling, and hydropic degeneration resulting in renal injury and hematuria. Because cantharidin is a powerful vesicant and irritant, oral/ophthalmic exposures can result in vesiculobullous lesions, mucosal edema, and keratoconjunctivitis (Barceloux, 2008; Knapp et al, 1999; Bertaux et al, 1988).
    B) CARDIAC
    1) There is a dose-related mitochondrial swelling with disruption of the cristae, appearance of intramitochondrial inclusion bodies and myofibril degeneration (Rabkin et al, 1979; Friesen et al, 1979)
    C) CNS
    1) Ecchymotic areas in the medulla, cerebellum, and pia were found (Oaks et al, 1960)
    D) LIVER
    1) Showed edematous and fatty changes (Oaks et al, 1960).
    2) A mouse study used radiolabeled cantharidin to show a specific liver binding site. They hypothesize that the site is a latent cytosolic protease which is activated by a conformational change initiated by combining with cantharidin (Graziano et al, 1987).

Physicochemical

Physical Characteristics

    A) Cantharidin Crystals are colorless, and odorless.
    B) Cantharidin is a solid, forming orthorhombic plates and scales (Budavari, 1996).

Ph

    1) No information found at the time of this review.

Molecular Weight

    A) 196.21

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) HEMOGLOBIN - Dogs given cantharides showed a decrease in hemoglobin, but no significant change in red blood cells (Nyazema et al, 1991).
    B) WHITE BLOOD CELLS - WBC increased after a dose of cantharides in dogs, reaching a peak at 6 hours (Nyazema et al, 1991).
    11.1.5) EQUINE/HORSE
    A) Horses may become exposed when eating alfalfa hay containing blister beetles. Reactions may be severe and fatal (Schoeb & Panciera, 1979) 1978).
    1) CLINICAL SIGNS - Colic, gastroenteritis, and frequent urination are associated with cantharidin's irritant effect. Renal dysfunction and hypocalcemia may develop (Ray et al, 1989). Gross hematuria may occur in later stages (Schmitz & Reagor, 1987).
    2) DIAGNOSIS -
    a) May be made by finding beetle parts in the gastrointestinal contents, detection of cantharidin in urine, gastrointestinal contents, or tissues (kidney) (Beasley et al, 1983).
    b) Improved methods for diagnosis of cantharidin or blister beetle toxicosis in animals involve partial purification of gastric content and urine extracts using silica cartridges; analysis is performed using capillary gas chromatography/mass spectrometry. Peak incidence has been noted in late summer and early fall (Ray et al, 1980; Ray et al, 1989).
    c) Analysis of stomach content and urine of horses and sheep with blister beetle poisoning using high performance liquid chromatography has proven valuable in diagnosis (Ray et al, 1980a).
    3) LABORATORY -
    a) In a study of horses given cantharidin, decreases in arterial oxygen tension, total protein, serum creatine kinase, arterial CO2, and plasma bicarbonate were noted in surviving horses during at least one 6-hour testing interval (Shawley & Rolf, 1984). Mild azotemia has also been reported in horses (Schmitz, 1989).
    b) ELECTROLYTE DEPLETION - There may be severe vomiting and diarrhea, which can lead to fluid and electrolyte depletion. In horses given cantharidin, decreases in total serum calcium, serum magnesium, and potassium were noted; calcium and magnesium levels were still significantly depressed at 48 hours (Shawley & Rolf, 1984; Schmitz, 1989).

Treatment

    11.2.1) SUMMARY
    A) HORSE
    1) Treatment of cantharidin toxicosis in horses is empiric and unrewarding (Anon, 1989).

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) HORSE
    1) LETHAL DOSE is less than 1 mg/kg (Ray et al, 1989).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) HORSE
    1) Treatment of cantharidin toxicosis in horses is empiric and unrewarding (Anon, 1989).

Other

    A) OTHER
    1) SPECIFIC TOXIN
    a) LABORATORY -
    1) Ray et al (1989) report a capillary gas chromatography mass spectrometry method of identifying cantharidin in urine and gastric contents of horses.
    2) Urine and gastric concentrations of cantharidin ranged from 0.0003 to 3.5 mcg/g during a 26-month period covering 53 episodes of cantharidin toxicosis in horses (Ray et al, 1989).

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