Cantharidin Poisoning Research Articles

Covalent Binding of Reactive Anhydride of Cantharidin to Biological Amines.

Cantharidin is a terpenoid from coleoptera beetles. Cantharidin has been used to treat molluscum contagiosum and some types of tumors. Cantharidin is highly toxic, and cantharidin poisoning and fatal cases have been reported worldwide. The mechanisms underlying cantharidin-induced toxicity remain unclear. Cantharidin contains anhydride, which may react with biologic amines. This study aimed to examine the chemical reactivity of cantharidin toward nucleophiles and characterize adducts of cantharidin with biologic amines in vitro and in mice. Here two types of conjugates were formed in the incubation of cantharidin under physiologic conditions with free amino acids, a mimic peptide, or amine-containing compounds, respectively. Amide-type conjugates were produced by the binding of cantharidin anhydride with the primary amino group of biologic amines. Imide-type conjugates were generated from the dehydration and cyclization of amide-type conjugates. The structure of the conjugates was characterized by using high-resolution mass spectrometry. We introduced the 14N/15N and 79Br/81Br isotope signatures to confirm the formation of conjugates using L-(ε)15N-lysine, L-lysine-15N2, and bromine-tagged hydrazine, respectively. The structure of imide conjugate was also confirmed by nuclear magnetic resonance experiments. Furthermore, the amide and imide conjugates of cantharidin with amino acids or N-acetyl-lysine were detected in mouse liver and urine. Cantharidin was found to modify lysine residue proteins in mouse liver. Pan-cytochrome P450 inhibitor 1-aminobenzotriazole significantly increased the urine cantharidin-N-acetyl-lysine conjugates, whereas it decreased cantharidin metabolites. In summary, cantharidin anhydride can covalently bind to biologic amines nonenzymatically, which facilitates a better understanding of the role of nonenzymatic reactivity in cantharidin poisoning. SIGNIFICANCE STATEMENT: Anhydride moiety of cantharidin can covalently bind to the primary amino group of biological amines nonenzymatically. Amide and imide conjugates were generated after the covalent binding of cantharidin anhydride with the primary amino groups of amino acids, a mimic peptide, and protein lysine residues. The structure of conjugates was confirmed by 14N/15N and 79Br/81Br isotope signatures using isotope-tagged reagents and nuclear magnetic resonance experiments. This study will facilitate the understanding of the role of nonenzymatic reactivity in cantharidin poisoning.

Multiorgan dysfunction syndrome due to high-dose cantharidin poisoning: A case report

BACKGROUND This report delves into the diagnostic and therapeutic journey undertaken by a patient with high-dose cantharidin poisoning and multiorgan dysfunction syndrome (MODS). Particular emphasis is placed on the comprehensive elucidation of the clinical manifestations of high-dose cantharidin poisoning, the intricate path to diagnosis, and the exploration of potential underlying mechanisms. CASE SUMMARY A patient taking 10 g of cantharidin powder orally subsequently developed MODS. The patient was treated with supportive care, fluid hydration and antibiotics, and hemoperfusion and hemofiltration therapy for 24 h and successfully recovered 8 d after hospital admission. Cantharidin poisoning can cause life-threatening MODS and is rare clinically. This case underscores the challenge in diagnosis and highlights the need for early clinical differentiation to facilitate accurate assessment and prompt intervention. CONCLUSION This article has reported and analyzed the clinical data, diagnosis, treatment, and prognosis of a case of high-dose cantharidin poisoning resulting in MODS and reviewed the relevant literature to improve the clinical understanding of this rare condition.

Children's Ingestion of Blister Beetles Causing Cantharidin Poisoning : Two pediatric cases in Saudi Arabia

Background: Cantharidin, a toxic substance produced by Meloidae (Coleoptera family) beetles, poses serious health risks upon ingestion, including renal impairment, hematemesis, altered consciousness, electrolyte imbalances, and hematuria. Case Report: This study presents two pediatric cases of cantharidin poisoning resulting from biting of Meloid beetles. Case 1 involved a 2-year-old exhibiting hematuria and vomiting, while case 2, a 9-month-old, presented with agitation, lethargy, and hematuria. Both cases required intensive care and supportive management. Conclusion: These cases highlight the clinical manifestations of cantharidin intoxication in children following exposure to Meloid beetles. Early recognition of symptoms, prompt medical intervention, and close monitoring are crucial in managing cantharidin poisoning, for which no specific antidote currently exists.

Research Progress on Multiple Organ Damage and Mechanism of Cantharidin Poisoning.

Cantharidin poisoning has been proven to cause multiple organ damage. Acute circulatory failure, acute renal failure, and multiple organ failure resulting from cantharidin poisoning are the main causes of death for patients with cantharidin poisoning. However, research on the damage of main target organs and mechanism of cantharidin poisoning is not clear. This paper reviews the latest toxicological and pathological research literatures at home and abroad related to cantharidin poisoning and comprehensively summarizes the latest research progress on the toxicological and pathological damage and mechanism of the digestive system, circulatory system, respiratory system, urinary system, reproductive system, skin mucosa, immune system, and nervous system after cantharidin poisoning, to provide reference for improving the molecular toxicological mechanism of cantharidin poisoning and decision-making in the clinical intervention of cantharidin poisoning.

Biomarkers of myocardial injury in rats after cantharidin poisoning: Application for postmortem diagnosis and estimation of postmortem interval

Postmortem diagnosis of cantharidin-induced myocardial injury and postmortem interval estimation (PMI) are the challenges in forensic science. Cardiac biomarkers play an important role in the prediction and diagnosis of myocardial injury and can be used to determine the PMI. Based on the evidence, we aimed to explore the biomarkers which may be used for the postmortem diagnosis of cantharidin-induced myocardial injury and PMI estimation using the study of the proteins expression of TN-T, VEGF and HIF-1α by ELISA. Results of this study suggested that postmortem pathological changes were difficult to identify due to the autolysis of myocardium 72 h after death in cantharidin poisoning group. The plasma levels of TN-T and HIF-1α/TN-T are cardiac biomarkers with higher diagnostic accuracy for postmortem diagnosis of cantharidin-induced myocardial injury, VEGF/HIF-1α promises to be a biomarker for PMI estimation. Further studies are needed to verify these biomarkers, based on population, for being a useful tool in postmortem diagnosis of cantharidin-induced myocardial injury and PMI estimation.

Cantharidin-induced acute hepatotoxicity: the role of TNF-α, IKK-α, Bcl-2, Bax and caspase3.

Cantharidin is of high medicinal value but has strong toxicity. Nowadays, multiple research has focused on the mechanism of its antitumor activity while research on toxicological profiles associated with cantharidin poisoning is still limited. Its hepatotoxicity has attracted attention recently for the crucial role of the liver in detoxification. Here, we aim to find a potential mechanism for cantharidin-induced acute hepatotoxicity with a view to assisting subsequent research or clinical use or detoxification. Twenty-one male Sprague-Dawley rats were randomly divided into control, low-dose (1.34 mg/kg) and high-dose (2.67 mg/kg) cantharidin exposure groups. We used hematoxylin-eosin to observe pathological changes and used immunofluorescent staining, western blotting and real-time quantitative polymerase chain reaction to detect the expression of the markers. The main pathological changes in livers of cantharidin-treated rats were necrosis, inflammatory infiltration and hemorrhage. We found coexpression of tumor necrosis factor alpha (TNF-α), IkappaB kinase-alpha (IKK-α) and caspase3 by immunofluorescent staining in livers of cantharidin-treated rats. Compared with the control, the levels of TNF-α, IKK-α and caspase3 increased significantly in the experimental groups (P < .05). The ratio of B-cell lymphoma-2 (Bcl-2)/Bax increased in the low-dose group but decreased in the high-dose group (P < .05). Cantharidin exposure raised IKK-α mRNA and caspase3 mRNA levels (P < .05). In conclusion, the participation of TNF-α, IKK-α, Bcl-2, Bax and caspase3 uncovered a novel mechanism underlying cantharidin-induced acute hepatotoxicity, and the mechanism needs to be studied further.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) determination of cantharidin in biological specimens and application to postmortem interval estimation in cantharidin poisoning

A rapid, sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination and quantification of cantharidin in rats liver and kidney. After grinding with methanol, the supernatant was determined by LC-MS/MS using an Thermo Accucore C18 column (100 mm×2.1 mm, 2.6 μm) with a gradient elution of 0.1% formic acid and 0.1% acetonitrile, and in the subsequent analysis using selected reaction monitoring mode, three ion transitions were monitored for analyte. The limit of detection (LOD) was 0.741 ng/ml and the limit of quantitation (LOQ) was 2.471 ng/ml. Good linearity (R2 = 0.9998) was observed for the analyte over the linear range (5–400 ng/ml). The LC-MS/MS method was applied to the analysis of rats liver and kidney in different postmortem intervals (6 h, 12 h, 24 h, 48 h, 72 h and 168 h after death) after a single dose (4 mg/kg) of cantharidin administration by gavage. At 72 h after death, the cantharidin concentration in livers and kidneys were significantly higher than that in other postmortem intervals. Linear regression equations between postmortem interval and lg postmortem cantharidin concentration in rats liver and kidney were Y = 0.007455*X + 1.332(R2 = 0.863) and Y = 0.002689*X + 1.433 (R2 = 0.115) respectively. The animal experiment demonstrated LC-MS/MS method can be used to determine the postmortem cantharidin concentration in rats liver and kidney and the determination of cantharidin in the rats liver after death has potential value for postmortem interval estimation in cantharidin poisoning.

Case Report: Cantharidin Poisoning after Insect Ingestion

AbstractBackground: Cantharidin is a toxic compound present in the Spanish Fly, commonly known as Blister Beetles, which is vesicant and toxic in nature. Clinical features of cantharidin poisoning include hematemesis, gross hematuria, and dysuria.Aim of the Study: To report a case of cantharidin poisoning in a child, after accidental ingestion of a blister beetle.Case Report: We report a case of accidental ingestion of blister beetle in an 18-month old girl, a resident of Aseer Region, Saudi Arabia, who was brought by her father with classical signs and symptoms of cantharidin poisoning, in-cluding hematemesis, abdominal pain, hematuria and suspected poisoning. Her condition was confirmed by her father who brought a similar insect to which was ingested by the patient. The patient recovered after being managed conservatively, serum electrolytes and blood gases were closely monitored. She was discharged after 7 days.Conclusion: Cantharidin poisoning cannot be diagnosed with particular clinical features, but a detailed and in-depth history combined with the presenting clinical symptoms should alert for this rare event. Health education for both the general population and the medical community about cantharidin poisoning may have some value in the prevention of such events.

Herbal Doesn't Equal to Harmless: A Case Report of Cantharidin Poisoning

Herbal Doesn't Equal to Harmless: A Case Report of Cantharidin Poisoning

Blister Mystery

A patient in Sri Lanka presented with a blistering rash in September (Figure 1). What is the diagnosis and how would you treat it? Dermatitis due to blister beetle. Blister beetles (Mylabris pustulata) (Figure 2) are common in South Asia. They are considered pests. Blister beetles are often seen in the vicinity of farmlands during August and September.1Iyer B.H. Guha P.C. Cantharidin from Mylabris pustulata, India.J Indian Inst Sci. 2013; 14: 31Google Scholar They are very sluggish during early morning, becoming more active after sunrise. Blister beetles secrete a yellow-colored oily substance from the leg joints.1Iyer B.H. Guha P.C. Cantharidin from Mylabris pustulata, India.J Indian Inst Sci. 2013; 14: 31Google Scholar, 2Ghoneim K.S. Enhancement of research interests in physiology and biochemistry of blister beetles (Coleoptera: Meloidae): a review.Int Res J Biochem Bioinforma. 2013; 3: 75-92Google Scholar, 3Nyazema N. Cantharidin poisoning: a review.South African Fam Pract. 1989; 10: 70-73Google Scholar This substance contains canthadrine, a skin irritant with high blistering capacity. Blister beetles do not sting or bite, but they release the blistering agent if they are pressed, brushed, or crushed.4James W.D. Berger T.G. Elston D.M. Andrew’s Diseases of the Skin: Clinical Dermatology.11th ed. Saunders Elsevier, Philadelphia2011Google Scholar Skin contact causes a burning, itching, or tingling sensation followed by the appearance of linear or irregular areas of erythema that later form vesicles (Figure 1).4James W.D. Berger T.G. Elston D.M. Andrew’s Diseases of the Skin: Clinical Dermatology.11th ed. Saunders Elsevier, Philadelphia2011Google Scholar, 5Padhi T. Mohanty P. Jena S. Sirka C. Mishra S. Clinicoepidemiological profile of 590 cases of beetle dermatitis in western Orissa.Indian J Dermatol Venereol Leprol. 2007; 73: 333Crossref PubMed Scopus (10) Google Scholar, 6Ajao A.M. Olalubi O.A. Aderolu I.S. et al.Investigation of blister beetle (Lytta vesicatoria) dermatitis outbreak and xontainment at Kwara State University students’ hostels.Sch J Appl Med Sci. 2016; 4: 460-468Google Scholar The vesicles rupture in a few days and form crusts. Secondary infection may occur. Lesions usually heal in a few days when treated with topical antibiotics.4James W.D. Berger T.G. Elston D.M. Andrew’s Diseases of the Skin: Clinical Dermatology.11th ed. Saunders Elsevier, Philadelphia2011Google Scholar, 5Padhi T. Mohanty P. Jena S. Sirka C. Mishra S. Clinicoepidemiological profile of 590 cases of beetle dermatitis in western Orissa.Indian J Dermatol Venereol Leprol. 2007; 73: 333Crossref PubMed Scopus (10) Google Scholar Early cleansing of the contact site with soap or alcohol helps to remove the canthadrine and may prevent the dermatitis.4James W.D. Berger T.G. Elston D.M. Andrew’s Diseases of the Skin: Clinical Dermatology.11th ed. Saunders Elsevier, Philadelphia2011Google Scholar Acknowledgments: I thank the editorial team of the Wilderness & Environmental Medicine journal for their continuous support to improve this manuscript. I acknowledge Dr OA Oluwasogo and Dr AM Ajao for the permission to use Figure 1 for this article.

Cantharidin revisited: a blistering defense of an ancient medicine.

Cantharidin, a vesicant produced by beetles in the order Coleoptera, has a long history in both folk and traditional medicine. In dermatology, topical cantharidin has long been used to treat warts and molluscum. In 1962, cantharidin lost Food and Drug Administration (FDA) approval owing to the failure of its manufacturers to submit data attesting to cantharidin's efficacy. However, it is expected that the FDA will soon include cantharidin on its "Bulk Substances List," which would permit physicians or pharmacists to compound cantharidin to be used in the office for individual patients. A comprehensive discussion of the origins, folk uses, current FDA status, current dermatologic uses, and effects of cantharidin poisoning has been compiled herein. No cases of systemic intoxication or scarring have been reported with the proper use of cantharidin by a physician. Cantharidin is a safe and valuable medication and should be readded to the dermatologic therapeutic armamentarium.

Cantharidin poisoning of emu chicks by ingestion of Pyrota insulata.

In April and May 1992, the Texas Veterinary Medical Diagnostic Laboratory (TVMDL) received for necropsy several frozen 1–3-month-old emu chicks from 1 ranching operation. Insects had swarmed to blooms on mesquite trees (Prosopis glandulosa) near the chick barn, and when a cool front arrived, lights were left on inside to encourage the chicks to seek shelter. As dusk fell, the insects were attracted to the lighted area, and they could be seen covering the floor of the barn and other surfaces accessible to the chicks. The history accompanying the birds described the chicks’ avid consumption of the insects. Some chicks remained clinically normal while others became ataxic, vomited beetles, became prostrate, and died. Some survived by vigorous treatment with oral fluids. Submissions to TVMDL consisted of proventricular contents, the frozen carcasses of 4 emu chicks, and a sample of the suspect insects. At necropsy, the esophagus of each bird was congested and edematous, and the proventricular serosa was hemorrhagic. The gizzard linings were sloughed, the intestinal contents were pink and the livers were pale. Tissue samples for histopathologic evaluation were fixed in 10% neutral buffered formalin, processed, embedded, sectioned and stained with hematoxylin and eosin (HE) prior to microscopic examination. Ingesta were examined under a dissecting microscope. Only 1 of the birds had a large volume of intact ingesta, which included fibrous plant material, small pebbles and 1 beetle about 1 cm long. Insect fragments were found in the proventricular and gizzard contents of 2 of the other chicks. Microscopically, the lesions varied in severity within each animal (Fig. 1). In some chicks, areas of the esophageal mucosa were overlaid with a thick coat of mucus (Fig. 1b). In others, there was multifocal epithelial ulceration with diffuse submucosal necrosis and thrombosis of small submucosal blood vessels (Fig. 1c–e). Catarrhal esophagitis and multifocal esophageal ulceration with underlying inflammation and necrosis were suggestive of exposure to a chemical irritant in a solid form, which was consistent with ingestion of a blister beetle, as opposed to a liquid irritant, which would have produced a more uniform lesion. Ingesta and insects were extracted and analyzed for can-

Ingestion of a Blister Beetle (Mecoidae Family)

Cantharidin, the most important active principle of Cantharis vesicatoria (Spanish fly), has a long history. It is a medieval medicine, considered over a hundred years ago as the most powerful medicine on the Materia Medica. It has been used as a skin irritant, vessicant, and abortifacient, and has long been wrongly considered an aphrodisiac.1 The following cases appear exceptional in that the source of the poison—the blister beetle itself—was ingested, resulting in the manifestations of cantharidin poisoning. CASE REPORT Two siblings were referred to the Royal Hospital in Muscat on March 30, 1994, for repeated episodes of blood-stained vomitus and passage of reddish-colored urine after ingestion of a beetle they caught in a garden.

Cantharidin poisoning associated with specific binding site in liver

Compared to the currently available therapeutic drugs for peripheral vascular diseases, agents that are selective for relaxing pulmonary circulation are scarce. The present study was undertaken, using isometric tension change measurement and whole-cell patch-clamp electrophysiology methods, to evaluate the vascular relaxation effect and the underlying mechanisms involved of two naturally found alkaloids: paeonol (2-hydroxy-4-methoxy-acetophenone), acetovanillone (4-hydroxy-3-methoxy-acetophenone) and the non-substituted analogue acetophenone on pulmonary artery of Sprague-Dawley rats. Cumulative administration (3 μM–1 mM) of acetophenone analogues resulted in a concentration-dependent relaxation of phenylephrine (1 μM) pre-contracted pulmonary artery. A relative order of inhibitory potency, estimated by comparing the concentration at which a 50% relaxation of phenylephrine-induced contraction observed was: acetovanillone > paeonol > acetophenone. Endothelial denudation and inhibition of nitric oxide synthase (with 20 μM NG-nitro-l-arginine methyl-ester) only moderately suppressed (17.6 ± 4.2%) acetovanillone- but not paeonol- or acetophenone-mediated maximum relaxation. Glibenclamide (3 μM, an ATP-sensitive K+ (IKATP) channel blocker) markedly attenuated all acetophenone analogues-mediated endothelium-independent relaxation. Neither cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL 12330A, 10 μM), iberiotoxin (300 nM), 4-aminopyridine (3 mM), (±)-propranolol (1 μM, a non-selective β-adrenoceptor blocker) nor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (3 μM, a guanylate cyclase inhibitor) altered endothelium-independent relaxation. In electrophysiological experiments using single pulmonary artery smooth muscle cells, acetovanillone, paeonol, acetophenone and cromakalim activated glibenclamide-sensitive, IKATP channels. In conclusion, our results demonstrate that acetophenone analogues caused pulmonary artery relaxation through opening of IKATP channels. In addition, acetovanillone-mediated pulmonary artery relaxation is partly depended on nitric oxide released from endothelium.

Cantharidin poisoning associated with specific binding site in liver

Cantharidin, the potent vesicant and toxicant of blister beetles, was prepared as a radioligand to probe its mechanism of action. [3H]Cantharidin interacts in a saturable and specific manner with a binding site in mouse liver cytosol with apparent Kd and Bmax values of 30 nM and 1.8 pmol/mg protein, respectively. Comparisons of cantharidic acid, the related herbicide endothal, and 20 other oxabicycloheptane-dicarboxylic acids show that their potency as inhibitors of [3H]cantharidin binding is closely correlated with their intraperitoneal toxicity to mice. This binding site is also inhibited invivo by toxic doses of cantharidin. The [3H]cantharidin binding site in mouse liver cytosol therefore represents, or serves as a model for, the site of toxic action of cantharidin and structurally-related compounds.

Structural and biochemical changes in tissues isolated from the cantharidin-poisoned rat with special emphasis upon hepatic subcellular particles

Male albino rats were poisoned with cantharidin by intraperitoneal injection. Extensive damage to the epithelium of all organs was noted by examination with the light microscope. The morphologic changes were uniform and reproducible. Examination of the hepatic cell with the electron microscope 5, 10, and 15 min post injection revealed early injury to the cell membrane, endoplasmic reticulum, and somewhat later to the mitochondria. The subcellular particles of the livers of poisoned and control rats were isolated. Phospholipid and cholesterol contents were analyzed after separation of the lipid components from these particles. No significant differences were noted. The chemical data do not preclude physical changes in the membrane structures resulting from cantharidin poisoning.

A case of cantharidin poisoning.

A case of cantharidin poisoning.