CANTHARIDIN (SPANISH FLY).
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Pharmacological & chemical properties of toxic substance mistakenly believed to be aphrodisiac.... More...
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Pharmacological & chemical properties of toxic substance mistakenly believed to be aphrodisiac.
Cantharidin (Spanish Fly) The pharmacologic potential of the substance, cantharides, has been known for thousands of years. This crude concoction is produced by grinding dried blister beetles. The best known blister beetle is Cantharis vesicatoria, or the Spanish fly. The agent responsible for cantharides' physiologic effects is the chemical, cantharidin. One of the many consequences of cantharidin ingestion is priapism. This finding has caused many to mistakenly assume that cantharides, or rather "Spanish fly," is an aphrodisiac. While the substance may in fact cause priapism, its primary pharmacologic effects are actually those of a potent toxin. People have used Cantharides powder since at least the time of Hippocrates (10:33). In fact, Hippocrates himself recommended
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Perhaps itwas during its employment as a therapeutic agent that the powder's effectson the genitourinary tract were first noticed. 215:64 ; 1971.----------------------- 15 However,two cases are on record where patients survived after ingestion of morethan 75 milligrams. Thatstudy postulates that alteration of the myocardial cell membrane ormitochondria leads to calcium overload (8:43). Burnett, J. Of the different effects that cantharidin has on specific organs,perhaps those most carefully investigated are its actions on the heart.One of the earliest cardiac symptoms associated with cantharidin poisoningis sinus tachycardia with normal blood pressure (11:445). In accordance with this belief, theyhave--in the past--attempted to treat blister forming diseases with blisterforming substances. L.; Murphy, M. Ray, A. Toxicosis is often theresult of the compound's misconceived aphrodisiac properties. A serious farm pest,E. In addition, it may also show petechial hemorrhages andsuperficial erosions, as it too loses much of its mucosal lining.Generally, this condition will give the patient a distressful feelinglocalized in the GI tract, with vomiting, hematemesis, retrosternal andlumbar pain, hematochezia, and tenesmus (11:446). W.; Friesen, J. One general approach to the patient includes: "(1) pain control,(2) control of vomiting, (3) introduction of a No. SouthAfrican Medical Journal. Since the Spanish fly is native to southern Europe, cantharides mayhave originally been derived from Cantharis vesicatoria (11:444). Oral administration of cantharidin may lead to excoriation, or eventotal mucosal loss. Cantharidin's toxic effects can be stronglyinfluenced by oils, which help to dissolve it and thereby increaseintestinal absorption. In humans, most cases of toxicityinvolve topical contact with the beetle extract (11:447). Terminal events are generally listed as priapism, abortion, coma,convulsions, and internal hemorrhage of the gastrointestinal and urinarytracts (11:445). Rosin, R. Cantharidin (Spanish Fly) The pharmacologic potential of the substance, cantharides, has beenknown for thousands of years. 5 :187-191; 1989.1 . In addition, gastric lavageand demulcents are recommended to remove any remaining drug. On the biosynthesis ofcantharidin. Cantharidin's blister-inducing ability has also been the subject ofexperimental research. American Journal of Veterinary Research. Two species, Epicauta vittata and E. It hasalso been suggested that cantharidin might prove therapeutically useful forcases of interstitial cystitis. In addition, the remainder of the urinary tract (ureter, bladder, andurethra) typically will also show congestion with engorgement of the mucousmembranes (11:446). Thus it is slowly excreted by the kidneys. Apparently, he had beenadvised to use something "sexy" to attract fish to his groundbait. Autopsy evidenceof myocardial damage has demonstrated multiple hemorrhages of 2 centimetersin diameter in the pericardium, as well as subendocardial hemorrhage in theinterventricular septum. SouthernMedical Journal. The researchconcluded that the initial T wave inversion was probably due to eithertoxic myocarditis or coronary insufficiency caused, in part, by peripheralvascular collapse (11:445). As a result, in that part of the world, the compound is one ofthe major poisons employed by criminals. With pelvic engorgement the ovaries may alsobecome engorged; thus their stromal supply may be stimulated toproliferate (11:447). In the eastern U.S., three-striped species of blister beetle includeE. Cantharidin is believed to circulate in the blood as an albuminate(11:445). Thus the entire mechanism behindcantharidin cardio-toxicity--like many other drug-induced cardiomyopathies--remains to be determined. 4 :22; 1987, July. Shortening of the cell cycle could be one mechanism by whichcantharidin causes the suprabasal cellular proliferation in the epidermisand, consequently, acantholysis. In fact, in1975, Fleckenstein and colleagues concluded that depletion of ATP was acritical component in the production of myocardial necrosis. Archives of Emergency Medicine. This finding has causedmany to mistakenly assume that cantharides, or rather "Spanish fly," is anaphrodisiac. Cantharides intoxication. In another investigation, Clausen (1979) found that cantharidinaffected cell regeneration (11:445). Over thousands of years cantharidin has found many uses. The lethal dose for cantharidin is not well established (11:444). One of the manyconsequences of cantharidin ingestion is priapism. M.; Ferris, J. North American blister beetles can grow to one inch in size. Literature Cited 1. Symptoms begin with the mucous membranes of themouth and esophagus becoming swollen and engorged; they may also showpatches of ulceration. Calcium-inducedmitochondrial damage is evidenced by intramitochondrial electron densebodies that are actually a calcium precipitate (8:43). Furthermore, these arrhythmias cannot beexplained by alterations in either blood pressure, electrolytes, or bloodgases (11:445). Peak incidences of cantharidin poisoning in animals areusually observed in late summer and early fall. 9. Cantharidin toxicosis may be an especially serious problem forlivestock (9:19 ). E. There have also been various attempts to manipulate the chemical'sblister-inducing ability for therapeutic effect. Death can occur within 12 hours (11:445). In the mice, the effect seemed todissipate after an average of two cycles. W.; Calton, G. More recent studies have been performed on convicted criminals(11:445). Neurological involvement may manifest itself as severe ataxia(sensory) and exaggerated deep tendon reflexes (11:447). Oneatypical case of cantharidin poisoning reported by Nicholls and Teare(1954) involved a 43-year-old man who was fishing. Furthermore, endoscopic investigations may showhemorrhagic bullous edema of the bladder (7:592). Cantharic acid is soluble only in fats, ether, and alcohol. More severe effects include crampy abdominal pain and nauseawith excess salivation. Cantharidin poisoning. Jama. Till, J. Fats shouldbe avoided since they enhance absorption (7:592). 14 Levine nasogastrictube with feeding of dilute milk, (4) monitoring for peripheral vascularcollapse and control with vasopressors, (5) management of possible acuterenal failure, and (6) replacement of electrolytes and fluids as needed(11:445). This research shows that there is also a dose-relatedmitochondrial swelling with disruption of the cristae, the appearance ofintramitochondrial inclusion bodies, and degeneration of the myofibrils. A.; Fung, H. However,in the presence of alkali, the acid does form soluble salts. The study concluded, therefore, that any therapeuticsuccess attributed to the remedy must result from psychological rather thanpharmacologic factors. Poisoning by topical application can potentially result in the fullspectrum of toxicity. This is primarily due to the widespread occurrenceof cantharidin-containing beetles. This may be followed by vomiting of blood-tingedgastric contents, increased urinary frequency, and diarrhea (7:592). The concoction reputedly helpedLouis XV and Ferdinand the Catholic overcome their "conjugal disinterests"(7:591). 5. This crude concoction is produced bygrinding dried blister beetles. Cantharidin: A valuable officetreatment of molluscum contagiosum. Over 2 of these species exist in withinthe United States. If necessary, to prevent aspiration of retained secretions, atracheotomy should be considered" (11:445). In fact, it is probably responsible for theevolutionary success of the blister beetle; there are, after all, thousandsof species of the insect which exist all over the world. All of thecompound's bonds are single except for the double bonds to two of itsoxygen atoms (3:1 19). Consequently, the stomach may becomecongested. Onset times are variable; symptoms may appear in two to three hours.At their mildest these symptoms might include local inflamation followed byblistering. Tromovitch, T. In SouthAfrica the substance can easily be obtained from local herbalists and witchdoctors. J.; Reagor, J. 58:1274; 1969. J.; Morgan, R. After 24 hours most ofthe Daphnia were dead. Southern Medical Journal.72:1 19; 1979. Typically, a 4 -kilogramhorse need only eat about 1 three-striped beetles to ingest a lethaldose. Funt, T. This resulted in an overall reduction of thenormal 54-hour cell cycle to 1 -12 hours (11:445). Blisterbeetles belong to the order Coleoptera (7:592). This neurologic complication may develop some timeafter intoxication and include dilated pupils, numbness in the hands andfeet, bilateral lower motor neuron lesions of the facial nerves, andprogressive distal weakness in the lower and upper limbs. Myocardial degeneration may also result incardiorespiratory collapse. In water, the chemical is extremely soluble (1:3 , ). C. 3rd; Muecke, E. In addition, a number of echocardiographic alterations withcantharidin poisoning have been observed. This may resultfrom handling the beetles, crushing them on the skin, or applying theirvesiculating fluid to the genitals as an aphrodisiac or medication (1:22). They ofteninfest tomato plants. pennsylvanica, are found in thesouth and southwestern parts of the country (1:22). While the substance may in fact cause priapism, its primarypharmacologic effects are actually those of a potent toxin. A. occidentalis (formerly classified together as E.lemniscata). An analysis of this therapeuticmodality by Leaman and Gorman (1989), however, failed to show anydifferences between patients who received cantharidin and those whoreceived placebo. Y. The compound has been employed with some successin the treatment of bilharzic calcification of the bladder mucosa. N. Hay otherthan alfalfa, however, may also become infested when it contains weedswhich the beetles can use for food (e.g., silverleaf nightshade). The agent responsible for cantharides'physiologic effects is the chemical, cantharidin. In the intact animal, however, arrhythmias are actually caused bymany different factors (8:43). While shaking the bottle, he managed tosoak his thumb. 7. This loss may extend from the tip of the tongue to thepylorus (11:446). J. Another organ strongly affected by cantharidin is the kidney. Theircoloration is variable (1:22). In addition, considerably smaller numbers of beetles can still causesevere problems. They primarily subsist on alfalfa hay. vittata is particularly abundant in the summer months. Thechemical's direct toxic effects include glomerular and tubular necrosiswithout interstitial involvement (7:592). The degree of thesesymptoms is related not only to the dose of poison ingested, but also tothe amount of fat and lipid material in the intestine (11:446). 2. 6. C.; Kyle, A. In South Africa,herbalists often prescribe cantharides for both the induction of abortion,and as an aphrodisiac (4:614). At present, there is no specific therapy for acute cantharidinintoxication. The companywhich manufacturers Cantharone claims that they have sold over 1,5 , milliliters of the product without hearing of a single case of systemicpoisoning. 74:444-447; 1981.12. While cantharidin causes priapism in men, it may leadto ovarian problems in women. Suchproliferation is the result of a very effective survival advantage: i.e.,the beetles are deadly poisonous. Findings in humans include ST elevation in leads II, III, V(F), V(2),and V(3), along with transient T wave inversions in V(2) and V(3), andwaxing and waning of T waves in III and aV(L) (11:445). British MedicalJournal. These insects aredistributed within six families and at least nine genera (1:22). Other organs damaged by cantharidin include the liver, spleen, andlungs. The chemical wasdissolved in water (1:3 , ) and the Daphnia were subsequently placed inthe solution (11:444). Cantharidin-inducedacantholysis. R.; Mehr, K. While the cantharides concoction has been known for centuries, itwasn't until 181 that cantharidin was first isolated by Robiquet (7:592).The compound, cantharidin (C1 H12 O4, or hexahydro-3,7-dimethyl-4,7,epoxyisobenzofuran-1,3,dione), is the volatile terpene anhydride of asimple aromatic acid, cantharic acid (11:444). Cantharidin poisoning with neurological complications. Furthermore, the application ofcalamine lotion containing a steriod may also prove beneficial (1:22). D. It is alsoslightly soluble in alcohols, and soluble in acetone at 1:4 dilutions(11:444). Ultimately these processesmay lead to a deficiency of high-energy phosphate compounds. 6:259-261; 1989. 3. Miscellaneous uses for cantharidin include the treatment of urinarytract ailments (7:592). During the Greco-Roman period cantharides was alsoused to treat pleurisy, pericarditis, and amenorrhea (11:444). Moreover,cantharidin poisoning has also been associated with a Guillain-Barre-likesyndrome (4:614-615). The precisechemical reactions required for the synthesis of cantharidin arecomplicated. M.; Gorman, D. 4. At autopsy, however, overallrenal damage is generally found to be extensive. People have used Cantharides powder since at least the time ofHippocrates (1 :33). J. In the United States, the rare reportable cases of cantharidintoxicosis usually involve poisoning by ingestion. Treatment, therefore, tends to be largely supportive(7:592). In rabbits, the presence,magnitude, and duration of ST depression, as well as the occurrence offatal arrhythmias, and survival time have all been found to be dose-related. Shortly thereafter, the man pricked the thumb on a hook.After sucking the wound to draw away the blood, he subsequently died. It subsequently affects other organs beforetraveling to the kidneys and intestines for secretion and excretion. Both .7% and .9% blistering solutions have been used for thetreatment of warts (2:1 19). Such derangement and denudation can occur with as smalla dose as 65 milligrams. It has been found, however, that the solutions are no moreeffective than other destructive means of wart removal, and perhaps not asgood as electrosurgery (11:445). This damage resultsin excessive activation of calcium-dependent intracellular adenosinetriphosphatases and mitochondrial destruction. Typically, the insects are found in fodderand other animal food. C. These solubility characteristics are important when dealing withdose-related toxicity. Journal of Pharmacology and ExperimentalTherapeutics. The result is clefting between the basal and epibasal layers to formblisters. Ithas been reported though to be as low as 1 milligrams (7:592). During the 18thcentury, cantharides use was widespread. Homeopathic physicians adhere to a principle oftreating like with like (5:259-261). The best known blister beetle is Cantharisvesicatoria, or the Spanish fly. Rabkin, S. The study observed shortened the G2phases of mitosis in mice. Later stages effects include erosion, hemorrhage,and total denudation (11:446). Pawlowsky and Stein quotedseveral values for cantharidin content for different species of blisterbeetle. They observed an average concentration of between 2.6 and 4.3parts per thousand (11:444). Presto, A. Etiologicagents, incidence, and improved diagnostic methods of cantharidintoxicosis in horses. A dose of Spanish fly. While accounts of cantharidin poisoning are scarce, the potential forit to occur is great. The alterationincludes an increase in the proportion of suprabasal cells synthesizingDNA. The .7% solution in equal parts of acetoneand flexible collodion USP is known as Cantharone (12:64 ). Cantharides use as a love potion is well rooted in folklore (7:591).As far back as the first century, the powder was advocated as anaphrodisiac by the Greek army physician, Dioscorides. The observation issignificant. Journal of Pharmaceutical Sciences. Cantharidin crystals are colorless, odorless, and glistening. Cantharidin. A. This particular sublethal effect depends on cantharidin concentration(6:419). J. Besides localblistering, systemic manifestations include hematuria, oliguria, myocardialdamage, CNS disease, and death (11:447). Theoretically, a dose of .5 milligrams could causedeath by suffocation if it became lodged in the throat (11:444). Hetherefore decided to soak the bait in a solution containing 65 milligramsof cantharidin dissolved in water. One hypothesis as to the mechanism by which the arrhythmias mightoccur has been suggested by Friesen and associates (1979) (11:445). Othercommon abnormal findings might be inflamed bullae on the glans penis, thepenile shaft, and the scrotum. The treatment of cantharidin-induced skin lesions consists ofcleansing with acetone, ether, fatty soap, or alcohol. The researchers performed their experiment on the smallfresh-water crustaceans, Daphnia magna (water fleas). Jama.214:591-592; 197 . Laboratory analyses may also show leukocytosis, proteinuria,hypotonic urine, renal necrosis, hypocalcemia, and elevated levels of serumbilirubin (1:22). 65:614-615; 1984. 1 :419- 423; 1988. Thus one homeopathic therapy, thought to acceleratehealing and alleviate pain in patients with minor burns, is the applicationof cantharidin-containing compounds. Pierard-Franchimont, C.; Pierard, G. The highest concentrations of the toxin is found in the beetles'ovaries, soft tissues, and blood (7:592). These insects can be found from Florida to New Jersey and mayrange as far as the midwestern and southwestern states to Colorado, andeven northeastern Mexico (9:189). It is certain that the chemical, cantharidin, produces very powerfulphysiologic effects. G. In nearly toxic doses, itsirritant effects cause priapism (permanent erection) in men, and pelviccongestion (with occasional uterine bleeding) in women. temexa and E. In fact, Hippocrates himself recommended it for thetreatment of dropsy. While no change was observed in the female waterfleas, the males proceeded to promptly ejaculate. American Journal of Dermatopathology. The aphrodisiac capability of cantharidin was analyzed by Vichowerand Cohen (1938). Guenther, H.; Ramstad, E.; Floss, H. A modelof cardiac arrhythmias and sudden death: cantharidin- induced toxiccardiomyopathy. The active ingredient ofcantharides, cantharidin, is a potent irritant. 8. Leaman, A. Finally, because of its very potent irritant action, cantharidin hasbeen used to manipulate the genitourinary tract. Harrisberg, J.; Deseta, J. Through the agesthese physiologic findings may have been misinterpreted as increasedsexuality. Cantharis in the early treatment ofminor burns. 21 :43-5 ; 1979 July. Blister beetles:"Spanish fly." Cutis. This suprabasalacantholysis is mediated by proteases and associated with modifications inthe cellular proliferation of the epidermis (6:419). The most common arrhythmias associated with cantharidin poisoning areventricular ectopic beats, ventricular tachycardia, ventricularfibrillation, and asystole. Theycan be identified by x-ray diffraction, melting point analyses, andcantharidin's ability to cause a skin reaction of pain and blistering uponcutaneous application (11:444). The poison is absorbed through the lipid layers ofthe epidermal cell membranes. S.; Majmudar, B. Basically, the compound consists of two rings--one benzene andone furan--with attached oxygen atoms and methyl groups. 4:33; 1967, October 7.11. C.; Cohen, L.; Temlett, J.; Milne,F. Its chemical structure suggests an isoprenoid origin(3:1 19). Moreover, research by Bodenstein foundconcentrations as high as 11 parts per thousand in the South Africanbeetle, Mylabridae. In the past, cantharidin was also employed in veterinary medicine.However, because its complications frequently include toxic nephritis andrenal failure, the chemical is no longer recommended for animals (7:592). It isestimated that worldwide there are over 2, different species ofcantharidin-containing beetles. These substanceswill dissolve and dilute the toxin (1:22).
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