BLISTER BEETLE INTOXICATION
Chem 377: Chemistry of Drugs and Poisons
HISTORY OF CANTHARIDIN:
Blister beetles produce cantharidin, which is toxic to people and animals. For centuries, cantharidin was prescribed as a cure for a variety of ailments. Spanishfly or cantharis, a preparation of dried meloid beetles, was thought to cure gout, carbuncles, rheumatism and many other medical disorders. The barbarisms practiced upon the American people during the nineteenth century by the application of cantharis beetles for all sorts of ailments, in addition to treating the misery endured by those who suffered in the Revolutionary War (Metcalf, 1962). The dried and crushed body of the beetle was used medically as an irritant and diuretic, but was also regarded as a potent aphrodisiac, especially for older gentlemen before its dangerous nature was recognized. Today, the toxic properties of cantharidin are more widely recognized and its use is largely restricted to veterinarians, who employ it as a counterirritant and blistering agent. (Davidson, 1987).
The earliest descriptions of the use of cantharidin as a medicine dates back to antiquity. Such people as Hippocrates, Celsus and Pliny mention the drug. The Roman empress Livia (58 B.C.-A.D. 29) slipped it into the food of other members of the imperial family to stimulate them into committing sexual indiscretions that could later be used against them (Metcalf, 1962).
STRUCTURE OF CANTHARIDIN:
Figure 1: Structure of the toxin
C10H12O4, Molecular Weight: 196.2024
Melting Point = 218 °C
SOURCE OF TOXIN:
Blister beetles are classified in the family Meloidae, order Coleoptera that range from the southwestern U.S. to the East Coast (http://agweb.okstate.edu/pearl/plantsoil/crops/f-2072.pdf). This family includes over 300 species in the United States and more than 2,500 worldwide. The genus Epicauta is the largest and contains many species that concern forage producers in semi-arid regions of the western United States.
The striped blister beetles are classified as Epicuata vittata, E. temexa and E. occidentalis, the black blister beetles are E. pennsylvanica and E. conferta, the spotted blister beetle is E. paradalis, and the Spanishfly (relative of the American blister beetle from Europe) is Lytta vesicatoria (http://encarta.msn.com). These beetles can be seen in figure 2.
These beetles carry a venomous substance diffused throughout their body, especially in their blood, rather than confined to particular glands. Blister beetles produce this substance called cantharidin; a potent chemical that possesses caustic or blistering properties when the insects are accidentally crushed or handled roughly. They are also poisonous if taken internally, as when livestock eat them while grazing (Aiello, 1998).
Figure 2: Various types of blister beetles
Cantharidin is an odorless, colorless compound that is soluble in various organic solvents, but only slightly soluble in water (Davidson, 1987). Cantharidin shown in figure 1 is a bicyclic terpenoid. This toxin is rapidly absorbed from the gastrointestinal tract and excreted in the urine. Cantharidin is the poisonous substance in blister beetles and is thought to protect the beetles from predation. It is comparable to cyanide and strychnine in toxicity (Aiello, 1998). The toxin is found in the hemolymph and gonads of the blister beetle. The content of cantharidin in the beetles ranges from 1-5% of dry weight (Carrel, 1993).
CANTHARIDIN PRODUCTION IN A BLISTER BEETLE:
Cantharidin is present in all ten-life stages of the complex metamorphosis shown in figure 5 of the blister beetle (Carrel, 1993). The first five larval stages accumulate cantharidin as they feed and grow in size. When disturbed, they exude cantharidin in a milky oral fluid, not in hemolymph which adult beetles reflexively discharge from leg joints. Two subsequent larval stages and the pupa do not feed, grow, regurgitate or change in their defensive reserves (110-mg catharidin/insect, regardless of sex) (Carrel, 1993). Adult beetles kept in isolation for 60-90 days exhibit a pronounced sexual dimorphism in cantharidin production. Cantharidin is produced only by male blister beetles and is stored until mating. The male beetle biosynthesizes about 17 mg of the toxin, representing 10% of his live weight (Carrel, 1993). Male beetles have the highest levels of the toxin and transfer cantharidin to the females during copulation.
Blister beetles are large, approximately 0.5-1.0 inch long, and can be of various colors (Metcalf, 1962). Their colors are beautiful; metallic green, blue, coppery or rose, spotted or striped yellow and black, while some are unmarked gray, brown or black. As shown in figure 3, these beetles have long, soft cylindrical bodies with a narrow prothorax forming a pronounced neck area that makes them easy to distinguish from other beetles.
Blister beetles are gregarious and often congregate in large swarms within alfalfa fields as seen in figure 4. These beetles do not migrate long distances. In alfalfa, they are often found within 50 yards of the field margin (Minks, 1988). The adults are foliage feeders that are quite destructive attacking many flowering plants, field and garden crops, clover, alfalfa, soybeans and weeds.
Figure 4: A typical swarm of striped blister beetles in alfalfa hay
Adult beetles mate and the females deposit fifty to several hundred eggs in the soil crevices during the summer. At hatching in 12 days, the active larvae are predators feeding on grasshopper and cricket eggs in order to reach maturity (Minks, 1988). The larvae are an important biological control agent for grasshoppers. During the next 25 to 28 days the larva molts four times, undergoing a remarkable series of changes in form and appearance known as hypermetamorphosis in figure 5 during which its legs, mouth parts, and other appendages grow progressively smaller (Davidson, 1987). The beetles emerge as adults in late spring and summer living for 4 to 6 weeks (Minks, 1988). The seasonal and peak occurrence of the different types of blister beetles in alfalfa varies (http://www.oznet.ksu.edu/library/entml2/mf959.pdf). They are very restless, active beetles that tend to feed together in swarms. Adults fly into fields, where they feed on foliage. Blister beetles are often worse in fields adjacent to weedy grassy areas that contain an abundance of grasshopper eggs.
Figure 5: The ten life stages of the blister beetle
MODE OF ACTION:
The Latin name of the beetle derives from the Greek word lytta, meaning rage and the Latin word vesica meaning blister (Carrel, 1993). This points to the main effects of poisonous doses resulting in internally mental illness and externally a vesicant action. It is highly irritating and causes acantholysis and vesicle formation when in contact with the skin or mucous membranes.
Cantharidin is a vesicant and a mucousal irritant which may cause oral and urinary bladder ulcers. After ingestion, it is absorbed from the GI tract and is rapidly excreted by the kidneys. Cantharidin inhibits phosphatase 2A which is involved in the control of cell proliferation, activity of membrane-associated channels and receptors, modulation of protein kinases and phosphatases (Eldridge, 1995).
ENVIRONMENTAL CONDITIONS SURROUNDING TOXICITY:
Blister beetles containing the toxin cantharidin can be incorporated with alfalfa during forage conservation. Blister beetle contaminated hay is almost always the result of beetles being crushed prior to baling. Beetles are killed by the crimper rollers and trapped in the hay. Remains of blister beetles may be concentrated in a small portion of the hay from a field. Beetles are also killed and trapped when forage is driven on before the beetles have had time to escape. If left alone, the vast majority of beetles leave alfalfa shortly after cutting.
Cantharidin inadvertently ingested with animal feed may cause illness or death in livestock. Even if the beetles are killed, the problem still exists. Cantharidin is a very stable compound that remains toxic in dead beetles. (Aiello, 1998). It was reported that blister beetles trapped in alfalfa hay were fed to valuable racehorses in Florida. Even though the beetles were dead the horses died of cantharidin poisoning (Guglick, 1996).
Cantharidin is highly toxic by ingestion, but can also be taken up through the skin and mucous membranes. The poisoning is called cantharidism and can consist of severe gastrointestinal disturbances and nephritis. Collapse occurs in several cases and death might follow.
A consumption of 1.6g of pulverized beetles containing the toxin led to death after 26 hours. Ten mg of pure cantharidin resulted in a fatality, whereas poisoning by 1.3mg did not (Davidson, 1987). Cantharidin is excreted by the kidney and will during excretion irritate the entire urinary tract. The irritation of the urethra will increase the blood flow to this region and might result in priapism, a persistent abnormal erection of the penis (Metcalf, 1962). It is likely that the priapism is the origin of the use of Spanish fly as an aphrodisiac.
Cantharidin is the sole toxin, but its concentration in beetles varies widely. Blister beetle intoxication and fatality is most commonly seen in equine, but comparable doses can poison cattle or sheep (Guglick, 1996). With such a variation in cantharidin content of beetles within the same species, it is difficult to determine the number of beetles to make a lethal dose. The cause of this variation is unknown, but partially relates to sex of the beetles, time of year and food source. The high variability in cantharidin content partially explains the wide range of beetles reported to cause death in horses. A single beetle or as many as 150 to 200 beetles have been reported as a lethal dose (Aiello, 1998). The minimal lethal oral dose in equids appears to be less than 1 mg/kg body weight (Guglick, 1996). The estimated number of beetles for a lethal dose of cantharidin vary depending on the type of blister beetle as well as the size of the horse that was infected (http://clay.agr.okstate.edu/alfalfa/webnews/blister.htm). The toxicity of cantharidin does not decrease in stored hay, and cantharidin is also toxic to people, dogs, cats, rabbits and rats.
Clinical signs are related to the amount of cantharidin ingested. The onset and duration of signs can vary from hours to days. Cantharidin can cause severe skin inflammation and blisters. The toxin is absorbed through the intestine and can cause symptoms ranging from mild depression or discomfort to severe pain, gastroenteritis, nephritis, shock and death. Massive doses of cantharidin cause shock and death within 6 hours (Helman, 1997). Smaller doses cause the following symptoms: colic, anorexia, depression, sweating, ulceration of oral mucosa, washing muzzle in water, soft stools, dysuria, elevated body temperature, increased respiration and heart rates, muscular rigidity, short-strided gait, collapse, dehydration and synchronous diaphragmatic flutter (SDF) due to hypocalcemia (Aiello, 1998).
There is frequent urination during the first 24 hours after ingestion, accompanied by inflammation of the urinary tract. This irritation may also result in secondary infection and bleeding. In addition calcium and magnesium levels in horses drastically lower and heart muscle tissues are destroyed. Typical signs are related to GI and urinary tract infection, endotoxemia and shock, hypocalcemia and myocardial dysfunction.
Acantholysis of the gastrointestinal tract (esophagus and nonglandular portion of stomach) as well as the urinary bladder is present. Gastritis and enterocolitis is evident characterized by mucosal hyperemia, hemorrhage, ulceration, edema and excessive fluid and edema (Aiello, 1998). Hemorrhagic and ulcerative cystitis along with vesication of the nonglandular portion of the stomach results.
Cantharidin poisoning can be identified through observed clinical signs along with gross and microscopic pathologic signs. Whether the horse has consumed alfalfa hay in the past may also help with the diagnosis to know if the horse was possibly exposed to blister beetles. Chemical analysis can also be performed for cantharidin. These methods include high-pressure liquid chromatography (HPLC) and gas chromatography of samples from the gastrointestinal content, urine and serum (Ray, 1989). Improved methods involve partial purification of urine and gastric content extracts, using silica cartridges, followed by analysis using gas chromatography and mass spectrometry. The concentration of cantharidin in urine becomes negligible in 3-4 days (Ray, 1980). Therefore urine should be collected early in the course of disease if it is to be analyzed for cantharidin content.
There exists no specific antidote for cantharidin poisoning. Management of blister beetles is difficult. Treatment thresholds have not been established and chemical controls often do not eliminate the problem because dead beetles can be picked up in the hay and more beetles can migrate into the field. The main focus should be centered on cantharidin removal, reduction of absorption and immediate symptomatic therapy.
The removal of cantharidin can be accomplished by removing alfalfa or suspected feed from the animals. Several insecticides are registered for blister beetle control such as Sevin and Methoxychlor (Aiello, 1998). Strip-spraying field edges may be the best approach when blister beetles are observed in adjacent areas. Reduction of the toxin can be accomplished through administration of activated charcoal and mineral oil. Symptomatic therapy includes administration of fluids to correct dehydration and promote diuresis, analgesics, calcium and magnesium replacement, and broad-spectrum antibiotics (Minks, 1988).
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