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1
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Campos-Sánchez JC, Guardiola FA, Esteban MÁ. In vitro immune-depression and anti-inflammatory activities of cantharidin on gilthead seabream (Sparus aurata) leucocytes activated by λ-carrageenan. FISH & SHELLFISH IMMUNOLOGY 2024; 148:109470. [PMID: 38442766 DOI: 10.1016/j.fsi.2024.109470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/07/2024]
Abstract
Cantharidin is a natural compound with known therapeutic applications in humans. The aim of this study was to investigate the in vitro effects of cantharidin on gilthead seabream (Sparus aurata) head kidney leucocytes (HKL) stimulated with λ-carrageenan. HKLs were incubated for 24 h with cantharidin (0, 2.5 and 5 μg mL-1) and λ-carrageenan (0 and 1000 μg mL-1). The results showed that HKL viability only decreased by 15.2% after incubated with 5 μg mL-1 of cantharidin and λ-carrageenan. Cantharidin increased the peroxidase activity of HKLs only when incubated in combination with λ-carrageenan. Besides this, cantharidin inhibited the respiratory burst and phagocytic activities. Furthermore, cantharidin induced morphological changes in HKLs (apoptotic and vacuolization signs) that were enhanced when incubated with λ-carrageenan. Considering the analysis of the selected gene expression studied in HKLs [NF-κB subunits (rela, relb, crel, nfkb1, nfkb2), proinflammatory cytokines (il1b, tnfa), anti-inflammatory cytokines (il10, tgfb) and caspases (casp1, casp3, casp8, casp9)], although λ-carrageenan up-regulated the expression of the proinflammatory gene il1b, λ-carrageenan and cantharidin down-regulated its expression in HKLs. In addition, cantharidin up-regulated casp3 and casp9 expression. The casp3 and casp9 gene expression was down-regulated while casp1 gene expression was up-regulated in HKLs incubated with both cantharidin and λ-carrageenan. All the effects of cantharidin are related to its inhibitory effect on protein phosphatases, which induce apoptosis at long exposure times, and minimize the effects of λ-carrageenan. The present results provide detailed insight into the immune-depressive and anti-inflammatory properties of cantharidin on immune cells, which could be of interest to the aquaculture sector.
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Affiliation(s)
- Jose Carlos Campos-Sánchez
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology Faculty of Biology, Campus Regional de Excelencia Internacional "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain
| | - Francisco A Guardiola
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology Faculty of Biology, Campus Regional de Excelencia Internacional "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain
| | - María Ángeles Esteban
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology Faculty of Biology, Campus Regional de Excelencia Internacional "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain.
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2
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Xu WL, Tang WJ, Yang WY, Sun LC, Zhang ZQ, Li W, Zang XX. Multiorgan dysfunction syndrome due to high-dose cantharidin poisoning: A case report. World J Clin Cases 2024; 12:2074-2078. [PMID: 38680272 PMCID: PMC11045515 DOI: 10.12998/wjcc.v12.i12.2074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/07/2024] [Accepted: 03/28/2024] [Indexed: 04/16/2024] Open
Abstract
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.
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Affiliation(s)
- Wan-Ling Xu
- Department of Emergency Medicine, First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Wen-Jing Tang
- Department of Emergency Medicine, First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Wei-Ying Yang
- Department of Emergency Medicine, First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Chao Sun
- Department of Emergency Medicine, First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Ze-Qun Zhang
- Department of Chinese Traditional Medicine, First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Wei Li
- Department of Emergency Medicine, First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Xiu-Xian Zang
- Department of Emergency Medicine, First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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3
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Yeung KA, Chai PR, Russell BL, Erickson TB. Avian Toxins and Poisoning Mechanisms. J Med Toxicol 2022; 18:321-333. [PMID: 35474563 PMCID: PMC9492810 DOI: 10.1007/s13181-022-00891-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/08/2022] [Accepted: 03/18/2022] [Indexed: 12/04/2022] Open
Abstract
All around the world, there are species of birds that have developed the ability to acquire toxic chemicals in their bodies making them less palatable or even lethal when consumed or contacted. Exposure to poisonous bird species is rare among humans, yet their poisons can produce serious clinical outcomes. In this study, we conducted a literature search focusing on seven avian species: the pitohuis (Pitohui spp.), blue-capped ifrita (Ifrita kowaldi), European quail (Cortunix corturnix coturnix), spur or spoor-winged goose (Plectropterus gambensis), North American ruffed grouse (Bonasa umbellus), Brush bronzewings (Phaps elegans), and European hoopoes and woodhoopoes (Upupa epops and Phoeniculus purpureus, respectively). We present the geographic distribution of each poisonous bird, toxin physiology and origin, clinical signs and symptoms of poisoning, cases of human toxicity if available and discuss the birds' ability to prevent self-intoxication. Our results suggest that most cases of contact with toxic birds produce mild symptoms as most of these birds apart from the European quail (C. c. corturnix) and North American ruffed grouse (B. umbellus) are not commonly consumed by humans. Furthermore, we discuss several methods of toxin acquisition in these bird species, which are mostly diet acquired apart from the hoopoes and woodhoopoes (Upupa and Phoeniculus spp.) who have a symbiotic relationship with chemical-producing bacteria in their uropygial glands. In summary, our study provides a comprehensive review of the toxic physiology, clinical manifestations, and evolutionary insight to avian toxins.
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Affiliation(s)
- Kara A Yeung
- Harvard Affiliated Emergency Medicine Residency (HAEMR) Program, Mass General Brigham, Boston, MA, USA
| | - Peter R Chai
- Department of Emergency Medicine, Division of Medical Toxicology, Mass General Brigham, Vining St. Neville House Boston, Boston, MA, 02115, USA
- The Fenway Institute, Boston, MA, USA
- The Koch Institute for Integrated Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Division of Psychosocial Oncology and Palliative Care, Dana Farber Cancer Institute, Boston, MA, USA
| | - Brendan L Russell
- Department of Emergency Medicine, Division of Medical Toxicology, Mass General Brigham, Vining St. Neville House Boston, Boston, MA, 02115, USA
| | - Timothy B Erickson
- Department of Emergency Medicine, Division of Medical Toxicology, Mass General Brigham, Vining St. Neville House Boston, Boston, MA, 02115, USA.
- Harvard Humanitarian Institute, Cambridge, MA, USA.
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4
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Campos-Sánchez JC, Guardiola FA, Esteban MÁ. In vitro effects of cantharidin on gilthead seabream (Sparus aurata) head-kidney leucocytes. FISH & SHELLFISH IMMUNOLOGY 2022; 123:20-35. [PMID: 35218974 DOI: 10.1016/j.fsi.2022.02.045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 12/30/2021] [Accepted: 02/21/2022] [Indexed: 06/14/2023]
Abstract
Cantharidin is a toxic vesicant terpene used in folk and traditional medicine due to its various therapeutic effects. Since there are no previous data on the effect of cantharidin in fish, this study aimed to investigate the in vitro related-inflammatory effects of cantharidin in gilthead seabream (Sparus aurata L.) head-kidney leucocytes (HKLs). In the first experiment, the HKLs were incubated with 0, 5 and 10 μg mL-1 of cantharidin for 24 h to delimit its possible toxic effects. In a second experiment, leucocytes were incubated with ranging concentrations from 0 to 10 μg mL-1 for 3, 6, or 12 h. Cell viability was higher in acidophilic granulocytes than in monocytes/macrophages and lymphocytes. Cantharidin caused apoptosis as was evidenced by transmission electron microscopy. In addition, cantharidin produced a time- and dose-dependent decrease of respiratory burst and phagocytic activities in HKLs, while their peroxidase activity was increased at 24 h of incubation with 5 and 10 μg mL-1 of cantharidin. Different changes in the gene expression were observed after incubation with cantharidin. While the gene expression of tnfa, il1b and crel was up-regulated in HKLs, the nfkb1 and igmh genes were down-regulated in comparison to the expression found in control HKLs. Present results offer a first view of the possible effects and action mechanisms of cantharidin in HKLs, as well as its implication in the inflammatory process, which could be of interest not only for basic research but also in the aquaculture sector.
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Affiliation(s)
- José Carlos Campos-Sánchez
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology. Faculty of Biology, Campus Regional de Excelencia Internacional "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain
| | - Francisco A Guardiola
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology. Faculty of Biology, Campus Regional de Excelencia Internacional "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain
| | - María Ángeles Esteban
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology. Faculty of Biology, Campus Regional de Excelencia Internacional "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain.
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5
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Köse A. A simple route for the synthesis of novel norcantharimide derivatives via acidolysis with hydrochloric acid
(gas). J Heterocycl Chem 2021. [DOI: 10.1002/jhet.4248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Aytekin Köse
- Department of Chemistry, Faculty of Science and Letters Aksaray University Aksaray Turkey
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6
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Özkan H, Adem Ş. Synthesis, Spectroscopic Characterizations of Novel Norcantharimides, Their ADME Properties and Docking Studies Against COVID-19 M pr°. ChemistrySelect 2020; 5:5422-5428. [PMID: 32518817 PMCID: PMC7272884 DOI: 10.1002/slct.202001123] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 04/27/2020] [Indexed: 01/05/2023]
Abstract
A series of novel Norcantharimide derivatives were synthesized and their structures were characterized by FTIR, 1H and 13C NMR spectroscopy as well as elemental analyses. The absorption, distribution, metabolism and excretion (ADME) properties of the synthesized molecules were investigated. The results obtained in silico demonstrated that these molecules can be considered as orally active drug candidates due to their physicochemical properties. Also, docking studies demonstrated that all derivatives exhibit a good theoretical affinity with MolDock Score in between 124-138 against the main protease of Coronavirus Disease 2019 (COVID-19 Mpr°) that caused worldwide epidemics. We believe that newly synthesized norcantharimide derivatives can guide many future studies in organic synthesis, medicine and pharmaceutical applications.
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Affiliation(s)
- Hamdi Özkan
- Department of Chemistry, Faculty of ScienceGazi University06500AnkaraTurkey
| | - Şevki Adem
- Department of Chemistry, Faculty of ScienceÇankırı Karatekin University18100ÇankırıTurkey
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7
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Nazim UM, Yin H, Park SY. Downregulation of c‑FLIP and upregulation of DR‑5 by cantharidin sensitizes TRAIL‑mediated apoptosis in prostate cancer cells via autophagy flux. Int J Mol Med 2020; 46:280-288. [PMID: 32319535 PMCID: PMC7255450 DOI: 10.3892/ijmm.2020.4566] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 03/06/2020] [Indexed: 11/17/2022] Open
Abstract
Tumor necrosis factor (TNF)-related apop-tosis-inducing ligand (TRAIL), a type II transmembrane protein, is a part of the TNF superfamily of cytokines. Cantharidin, a type of terpenoid, is extracted from the blister beetles (Mylabris genus) used in Traditional Chinese Medicine. Cantharidin elicits antibiotic, antiviral and antitumor effects, and can affect the immune response. The present study demonstrated that a cantharidin and TRAIL combination treatment regimen elicited a synergistic outcome in TRAIL-resistant DU145 cells. Notably, it was also identified that cantharidin treatment initiated the downregulation of cellular FLICE-like inhibitory protein (c-FLIP) and upregulation of death receptor 5 (DR-5), and sensitized cells to TRAIL-mediated apoptosis by initiating autophagy flux. In addition, cantharidin treatment increased lipid-modified microtubule-associated proteins 1A/1B light chain 3B expression and significantly attenuated sequestosome 1 expression. Attenuation of autophagy flux by a specific inhibitor such as chloroquine and genetic modification using ATG5 small interfering RNA abrogated the cantharidin-mediated TRAIL-induced apoptosis. Overall, the results of the present study revealed that cantharidin effectively sensitized cells to TRAIL-mediated apoptosis and its effects are likely to be mediated by autophagy, the downregulation of c-FLIP and the upregulation of DR-5. They also suggested that the combination of cantharidin and TRAIL may be a successful therapeutic strategy for TRAIL-resistant prostate cancer.
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Affiliation(s)
- Uddin Md Nazim
- Department of Veterinary Medicine, Biosafety Research Institute, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk 54596, Republic of Korea
| | - Honghua Yin
- Department of Veterinary Medicine, Biosafety Research Institute, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk 54596, Republic of Korea
| | - Sang-Youel Park
- Department of Veterinary Medicine, Biosafety Research Institute, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk 54596, Republic of Korea
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8
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Zeng Y, Guo Y, Zhang Y, Wang X, Jiang Y, Yang D. Rapid profiling of cantharidin analogs in Mylabris phalerata Pallas by ultra-performance liquid chromatography-quadrupole time-of-flight-tandem mass spectrometry. Biomed Chromatogr 2020; 34:e4801. [PMID: 31999361 DOI: 10.1002/bmc.4801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 01/03/2020] [Accepted: 01/28/2020] [Indexed: 12/18/2022]
Abstract
We evaluated the protective effect and toxicity of extracts from Mylabris phalerata Pallas by measuring the activated partial thromboplastin time, prothrombin time, venous thrombosis and acute toxicity in rats. Results showed the petroleum ether and water fractions of M. phalerata inhibited thrombosis but hardly prolonged the activated partial thromboplastin time and prothrombin time in rats. The trichloromethane fraction had obvious toxicity with an LD50 of 0.2 g/kg in vivo, and contained many cantharidin analogs (CAs) by ultra-performance liquid chromatography-quadrupole ion trap-tandem mass spectrometry (UPLC-QTRAP-MS/MS). CAs are the major potential bioactivity constituent in M. phalerata. An effective and reliable UPLC-QTRAP-MS/MS method was successfully developed to separate and identify CAs. The fragmentation patterns of five purified compounds were applied to elucidate the structure of their analogs. Thirty-four CAs were characterized or tentatively identified, eight of which are proposed to be novel compounds (13-17, 20, 21, 23), and their fragmentation patterns were investigated for the first time. Most importantly, a rapid and reliable UPLC-MS method was developed to identify the CAs of M. phalerata. This method has contributed to the discovery of most of these unknown analogs or their metabolites in M. phalerata effectively and quickly, and does not rely on limited chemical structural diversity libraries.
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Affiliation(s)
- Yaobo Zeng
- Chongqing Academy of Chinese Materia Medica, People's Republic of China
| | - Yanlei Guo
- Chongqing Academy of Chinese Materia Medica, People's Republic of China
| | - Yi Zhang
- Chongqing Academy of Chinese Materia Medica, People's Republic of China
| | - Xianying Wang
- Chongqing Academy of Chinese Materia Medica, People's Republic of China
| | - Yao Jiang
- Chongqing Academy of Chinese Materia Medica, People's Republic of China
| | - Dajian Yang
- Chongqing Academy of Chinese Materia Medica, People's Republic of China.,Comprehensive Health Center of Chongqing Research Institute of Traditional Chinese Medicine, People's Republic of China
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9
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Chen CC, Chueh FS, Peng SF, Huang WW, Tsai CH, Tsai FJ, Huang CY, Tang CH, Yang JS, Hsu YM, Yin MC, Huang YP, Chung JG. Cantharidin decreased viable cell number in human osteosarcoma U-2 OS cells through G 2/M phase arrest and induction of cell apoptosis. Biosci Biotechnol Biochem 2019; 83:1912-1923. [PMID: 31187696 DOI: 10.1080/09168451.2019.1627182] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cantharidin (CTD), a sesquiterpenoid bioactive substance, has been reported to exhibit anticancer activity against various types of cancer cells. The aim of the present study was to investigate the apoptosis effects and the underlying mechanisms of CTD on osteosarcoma U-2 OS cells. Results showed that CTD induced cell morphologic changes, reduced total viable cells, induced DNA damage, and G2/M phase arrest. CTD increased the production of reactive oxygen species and Ca2+, and elevated the activities of caspase-3 and -9, but decreased the level of mitochondrial membrane potential. Furthermore, CTD increased the ROS- and ER stress-associated protein expressions and increased the levels of pro-apoptosis-associated proteins, but decreased that of anti-apoptosis-associated proteins. Based on these observations, we suggested that CTD decreased cell number through G2/M phase arrest and the induction of cell apoptosis in U-2 OS cells and CTD could be a potential candidate for osteosarcoma treatments.
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Affiliation(s)
- Chia-Ching Chen
- Department of Biological Science and Technology, China Medical University , Taichung , Taiwan
| | - Fu-Shin Chueh
- Department of Food Nutrition and Health Biotechnology, Asia University , Taichung , Taiwan
| | - Shu-Fen Peng
- Department of Biological Science and Technology, China Medical University , Taichung , Taiwan
| | - Wen-Wen Huang
- Department of Biological Science and Technology, China Medical University , Taichung , Taiwan
| | - Chang-Hai Tsai
- China Medical University Children's Hospital, China Medical University , Taichung , Taiwan.,Department of Healthcare Administration, Asia University , Taichung , Taiwan
| | - Fuu-Jen Tsai
- Department of Healthcare Administration, Asia University , Taichung , Taiwan.,School of Chinese Medicine, College of Chinese Medicine, China Medical University , Taichung , Taiwan
| | - Chih-Yang Huang
- Graduate Institute of Biomedical Sciences, China Medical University , Taichung , Taiwan.,Graduate Institute of Chinese Medical Science, China Medical University , Taichung , Taiwan.,Chinese Medicine Research Center, China Medical University , Taichung , Taiwan.,Department of Pharmacology, School of Medicine, China Medical University , Taichung , Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University , Taichung , Taiwan.,Department of Physiology, College of Medicine, China Medical University , Taichung , Taiwan.,Department of Biotechnology, College of Medical and Health Science, Asia University , Taichung , Taiwan
| | - Chih-Hsin Tang
- Chinese Medicine Research Center, China Medical University , Taichung , Taiwan.,Department of Pharmacology, School of Medicine, China Medical University , Taichung , Taiwan.,Department of Biotechnology, College of Medical and Health Science, Asia University , Taichung , Taiwan
| | - Jai-Sing Yang
- Department of Medical Research, China Medical University Hospital, China Medical University , Taichung , Taiwan
| | - Yuan-Man Hsu
- Department of Biological Science and Technology, China Medical University , Taichung , Taiwan
| | - Mei-Chin Yin
- Department of Food Nutrition and Health Biotechnology, Asia University , Taichung , Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University , Taichung , Taiwan
| | - Yi-Ping Huang
- Department of Physiology, College of Medicine, China Medical University , Taichung , Taiwan
| | - Jing-Gung Chung
- Department of Biological Science and Technology, China Medical University , Taichung , Taiwan.,Department of Biotechnology, College of Medical and Health Science, Asia University , Taichung , Taiwan
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10
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Antiparasitic Properties of Cantharidin and the Blister Beetle Berberomeloe majalis (Coleoptera: Meloidae). Toxins (Basel) 2019; 11:toxins11040234. [PMID: 31013660 PMCID: PMC6521026 DOI: 10.3390/toxins11040234] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 04/16/2019] [Accepted: 04/18/2019] [Indexed: 12/17/2022] Open
Abstract
Cantharidin (CTD) is a toxic monoterpene produced by blister beetles (Fam. Meloidae) as a chemical defense against predators. Although CTD is highly poisonous to many predator species, some have evolved the ability to feed on poisonous Meloidae, or otherwise beneficially use blister beetles. Great Bustards, Otis tarda, eat CTD-containing Berberomeloe majalis blister beetles, and it has been hypothesized that beetle consumption by these birds reduces parasite load (a case of self-medication). We examined this hypothesis by testing diverse organisms against CTD and extracts of B. majalis hemolymph and bodies. Our results show that all three preparations (CTD and extracts of B. majalis) were toxic to a protozoan (Trichomonas vaginalis), a nematode (Meloidogyne javanica), two insects (Myzus persicae and Rhopalosiphum padi) and a tick (Hyalomma lusitanicum). This not only supports the anti-parasitic hypothesis for beetle consumption, but suggests potential new roles for CTD, under certain conditions.
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11
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12
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Synthesis, crystal structure, spectroscopic properties and potential anti-cancerous activities of four unsaturated bis-norcantharimides. J Mol Struct 2016. [DOI: 10.1016/j.molstruc.2016.02.093] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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13
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Wang Y, Sun W, Zha S, Wang H, Zhang Y. Synthesis and Biological Evaluation of Norcantharidin Derivatives Possessing an Aromatic Amine Moiety as Antifungal Agents. Molecules 2015; 20:21464-80. [PMID: 26633341 PMCID: PMC6331962 DOI: 10.3390/molecules201219782] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 11/26/2015] [Accepted: 11/30/2015] [Indexed: 01/19/2023] Open
Abstract
Based on the structure of naturally produced cantharidin, different arylamine groups were linked to the norcantharidin scaffold to provide thirty six compounds. Their structures were confirmed by melting point, ¹H-NMR, (13)C-NMR and HRMS-ESI studies. These synthetic compounds were tested as fungistatic agents against eight phytopathogenic fungi using the mycelium growth rate method. Of these thirty six derivatives, seven displayed stronger antifungal activity than did norcantharidin, seven showed higher activity than did cantharidin and three exhibited more significant activity than that of thiabendazole. In particular, 3-(3'-chloro-phenyl)carbamoyl norcantharidate II-8 showed the most significant fungicidal activity against Sclerotinia fructigena and S. sclerotiorum, with IC50 values of 0.88 and 0.97 μg/mL, respectively. The preliminary structure-activity relationship data of these compounds revealed that: (1) the benzene ring is critical for the improvement of the spectrum of antifungal activity (3-phenylcarbamoyl norcantharidate II-1 vs norcantharidin and cantharidin); (2) among the three sites, including the C-2', C-3' and C-4' positions of the phenyl ring, the presence of a halogen atom at the C-3'position of the benzene ring caused the most significant increase in antifungal activity; (3) compounds with strongly electron-drawing or electron-donating groups substitutions were found to have a poor antifungal activity; and (4) compared with fluorine, bromine and iodine, chlorine substituted at the C-3' position of the benzene ring most greatly promoted fungistatic activity. Thus, compound II-8 has emerged as new lead structure for the development of new fungicides.
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Affiliation(s)
- Yang Wang
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A & F University, Yangling 712100, China.
| | - Wenbo Sun
- Key Laboratory of Plant Protection Resources and Pest Management, Ministry of Education, Northwest A & F University, Yangling 712100, China.
| | - Shunqing Zha
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A & F University, Yangling 712100, China.
| | - Huan Wang
- Key Laboratory of Plant Protection Resources and Pest Management, Ministry of Education, Northwest A & F University, Yangling 712100, China.
| | - Yalin Zhang
- Key Laboratory of Plant Protection Resources and Pest Management, Ministry of Education, Northwest A & F University, Yangling 712100, China.
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14
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Males of a strongly polygynous species consume more poisonous food than females. PLoS One 2014; 9:e111057. [PMID: 25337911 PMCID: PMC4206510 DOI: 10.1371/journal.pone.0111057] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 09/28/2014] [Indexed: 11/19/2022] Open
Abstract
We present evidence of a possible case of self-medication in a lekking bird, the great bustard Otis tarda. Great bustards consumed blister beetles (Meloidae), in spite of the fact that they contain cantharidin, a highly toxic compound that is lethal in moderate doses. In addition to anthelminthic properties, cantharidin was effective against gastrointestinal bacteria that cause sexually-transmitted diseases. Although both sexes consumed blister beetles during the mating season, only males selected them among all available insects, and ingested more and larger beetles than females. The male-biased consumption suggests that males could use cantharidin to reduce their parasite load and increase their sexual attractiveness. This plausibly explains the intense cloaca display males perform to approaching females, and the meticulous inspection females conduct of the male's cloaca, a behaviour only observed in this and another similar species of the bustard family. A white, clean cloaca with no infection symptoms (e.g., diarrhoea) is an honest signal of both, resistance to cantharidin and absence of parasites, and represents a reliable indicator of the male quality to the extremely choosy females. Our results do not definitely prove, but certainly strongly suggest that cantharidin, obtained by consumption of blister beetles, acts in great bustards as an oral anti-microbial and pathogen-limiting compound, and that males ingest these poisonous insects to increase their mating success, pointing out that self-medication might have been overlooked as a sexually-selected mechanism enhancing male fitness.
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Liu M, Ma X, Jin Z, Li W, Guo M, Li F. Determination and pharmacokinetic study of the diacid metabolite of norcantharidin in beagle plasma by use of liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem 2013; 405:9273-83. [PMID: 24096565 DOI: 10.1007/s00216-013-7300-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 06/24/2013] [Accepted: 08/08/2013] [Indexed: 01/20/2023]
Abstract
Because norcantharidin (NCTD) is unstable and subject to ring opening and hydrolysis, the diacid metabolite of norcantharidin (DM-NCTD) is the stable form of NCTD found in normal saline solution. Conversion of NCTD to DM-NCTD is almost 100%, making it possible to determine and investigate the pharmacokinetics of DM-NCTD converted from NCTD. In this paper, a sensitive, simple and selective liquid chromatographic-tandem mass spectrometric method was developed and validated for determination of DM-NCTD in beagle plasma. DM-NCTD was detected in multiple-reaction monitoring (MRM) mode by using the dehydrated ion 169.3 as precursor ion and its product ion 123.1 as the detected ion. Ribavirin was used as internal standard and detected in MRM mode by use of precursor ions, resulting in a product ion transition of m/z 267.1 → 135.1. This method was successfully used for a pharmacokinetic study of DM-NCTD in beagles after intravenous administration of DM-NCTD in normal saline solution at doses of 0.39, 0.78, and 1.6 mg kg(-1). DM-NCTD had dose-dependent kinetics across the dosage range investigated, with enhanced T(1/2α) and AUC(0-12) and apparently decreasing V(d) and CL with increasing dosage. After single-dose administration, T(1/2α) ranged from 0.20 to 0.55 h, AUC(0-12) from 1.81 to 43.6 μg mL(-1) h(-1), V(d) from 228 to 55.9 mL kg(-1), and CL from 220 to 36.5 mL kg(-1) h(-1) (P < 0.01). The results indicated nonlinear pharmacokinetic behavior of DM-NCTD in beagles, suggesting that the risk of DM-NCTD in normal saline solution intoxication may be non-proportionally increased at higher doses.
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Affiliation(s)
- Minchen Liu
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, No. 548, Binwen Road, 310053, Hangzhou, China
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Percino-Daniel N, Buckley D, García-París M. Pharmacological properties of blister beetles (Coleoptera: Meloidae) promoted their integration into the cultural heritage of native rural Spain as inferred by vernacular names diversity, traditions, and mitochondrial DNA. JOURNAL OF ETHNOPHARMACOLOGY 2013; 147:570-83. [PMID: 23538164 DOI: 10.1016/j.jep.2013.03.037] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 02/12/2013] [Accepted: 03/10/2013] [Indexed: 05/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Beetles of the family Meloidae (blister beetles) are often reported in pharmacological literature because of their content of cantharidin. Cantharidin has a long history in human medicine and was commonly applied in the 19th and the early 20th centuries, although its use has been progressively abandoned since then. Contrary to most, even common, large species of Coleoptera, blister beetles of the genera Berberomeloe, Physomeloe and to a lesser extent Meloe, are usually recognized and often incorporated into local folk taxonomy by inhabitants of rural areas in Spain. AIM OF THE STUDY To demonstrate the role that pharmacological properties of blister beetles must have played in their integration in the culture of early Iberian human societies, but also in the preservation of their identity until today, a rare case for Spanish insects. To achieve this purpose we document the diversity of vernacular names applied in rural areas of Spain, and we determine, using molecular data, the antiquity of the presence of two species of the better-known blister beetle in rural Spain, Berberomeloe majalis and Berberomeloe insignis. MATERIALS AND METHODS We try to document the extent of traditional knowledge of meloid beetles in rural areas by interviewing about 120 people from villages in central and southern Spain. We also use mitochondrial DNA sequences (Cytochrome Oxidase I and 16SrRNA) obtained from several populations of two species of the better known blister beetle in rural Spain, Berberomeloe majalis and Berberomeloe insignis, to determine whether these beetles were already present in the Iberian Peninsula when earlier ancient cultures were developing. RESULTS Our results show that, based on mitochondrial DNA, blister beetles of the genus Berberomeloe were present in the Iberian Peninsula long before humans arrived, so ancient Iberian cultures were in contact with the same beetle species occurring now in rural areas. On the other hand, people interviewed in rural communities provided us with more than 28 different vernacular names, a few short songs incorporated to local folklore, and some therapeutic uses. CONCLUSIONS Current knowledge of blister beetles of the family Meloidae in rural Spain was likely developed as a consequence of their pharmacological properties; we hypothesize this knowledge was inherited from ancient pre-Christian Iberian native cultures as part of their traditional therapeutic traditions. It is possible then, that current vernacular names and traditional songs are the only remnants of an ancient knowledge of pharmacological uses of meloid beetles, verbally transmitted from the ancestral cultures to modern day rural Spain. Our work suggests that this legacy, part of the European Cultural Heritage, is disappearing fast, in parallel to the loss of traditional agricultural techniques.
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Affiliation(s)
- Nohemí Percino-Daniel
- Museo Nacional de Ciencias Naturales, MNCN-CSIC, José Gutiérrez Abascal, 2, 28006 Madrid, Spain
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Tarleton M, Gilbert J, Sakoff JA, McCluskey A. Synthesis and anticancer activity of a series of norcantharidin analogues. Eur J Med Chem 2012; 54:573-81. [PMID: 22796041 DOI: 10.1016/j.ejmech.2012.06.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Revised: 05/29/2012] [Accepted: 06/05/2012] [Indexed: 01/04/2023]
Abstract
Cantharidin (1) and norcantharidin (2) display high levels of anticancer activity against a broad range of tumour cell lines. Synthetic manipulation of norcantharidin yields (3S,3aR,4S,7R,7aS)-3-hydroxyhexahydro-4,7-epoxyisobenzofuran-1(3H)-one (3), which also displays a high level of anticancer activity against tumour cells but interestingly, shows selectivity towards HT29 (colon; GI(50) = 14 μM) and SJ-G2 (glioblastoma; GI(50) = 15 μM) cell lines. Substitution at the hydroxyl group of the cyclic lactone within (3) produces a diasteromeric pair of products that have no difference in cytotoxicity over the cell lines tested. Incorporation of an isopropyl tail at this position (16) produced the most promising compound of this series to date, with strong selectivity towards HT29 (colon; GI(50) = 19 μM) and SJ-G2 (glioblastoma; GI(50) = 21 μM) cell lines but completely void of any activity against the remaining tumour cell lines (GI(50) > 100 μM), as per the parent molecule. We also discovered that the introduction of a terminal phosphate moiety (28) at the same position produced a different trend in cytotoxicity with strong activity in BE2-C (neuroblastoma; GI(50) = 9 μM) cells; suggestive of an alternate mode of action.
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Affiliation(s)
- Mark Tarleton
- Chemistry, Centre for Chemical Biology, School of Environmental & Life Sciences, University of Newcastle, University Drive, Callaghan NSW 2308, Australia
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18
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Browne SG. Cantharidin Poisoning Due to a "Blister Beetle". BRITISH MEDICAL JOURNAL 2011; 2:1290-1. [PMID: 20788974 DOI: 10.1136/bmj.2.5208.1290] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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20
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Bajsa J, McCluskey A, Gordon CP, Stewart SG, Hill TA, Sahu R, Duke SO, Tekwani BL. The antiplasmodial activity of norcantharidin analogs. Bioorg Med Chem Lett 2010; 20:6688-95. [PMID: 20888768 DOI: 10.1016/j.bmcl.2010.09.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2010] [Revised: 08/31/2010] [Accepted: 09/01/2010] [Indexed: 12/22/2022]
Abstract
The antiplasmodial activities of sixty norcantharidin analogs were tested in vitro against a chloroquine sensitive (D6, Sierra Leone) and chloroquine resistant (W2) strains of Plasmodium falciparum. Forty analogs returned IC(50) values <500 μM against at least one of the P. falciparum strains examined. The ring open compound 24 ((1S,4R)-3-(allylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid) is the most active aliphatic analog (D6 IC(50)=3.0±0.0 and W2 IC(50)=3.0±0.8 μM) with a 20-fold enhancement relative to norcantharidin. Surprisingly, seven norcantharimides also displayed good antiplasmodial activity with the most potent, 5 returning D6=8.9±0.9 and W2 IC(50)=12.5±2.2 μM, representing a fivefold enhancement over norcantharidin.
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Affiliation(s)
- Joanna Bajsa
- USDA, ARS, Natural Products Utilization Research Unit, University, MS 38677, USA.
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21
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Mebs D, Pogoda W, Schneider M, Kauert G. Cantharidin and demethylcantharidin (palasonin) content of blister beetles (Coleoptera: Meloidae) from southern Africa. Toxicon 2009; 53:466-8. [DOI: 10.1016/j.toxicon.2009.01.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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22
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Huan SKH, Lee HH, Liu DZ, Wu CC, Wang CC. Cantharidin-induced cytotoxicity and cyclooxygenase 2 expression in human bladder carcinoma cell line. Toxicology 2006; 223:136-43. [PMID: 16697099 DOI: 10.1016/j.tox.2006.03.012] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2006] [Revised: 03/14/2006] [Accepted: 03/15/2006] [Indexed: 11/27/2022]
Abstract
Mylabris is used in clinical therapy, but is always accompanied by cystitis. The toxic effects of mylabris on bladder are attributed to its active principle: cantharidin. In the present study, we explored how cantharidin induces cytotoxicity in the bladder. Human bladder carcinoma cell line T 24 cells were used as target cells, and human colon carcinoma HT 29 cells as native cells. Cantharidin exhibited acute cytotoxicity in the T 24 cells, and IC(50) was 21.8, 11.2 and 4.6 microM after treatment for 6, 24 and 48 h, respectively. The cytotoxicity of cantharidin was not significantly enhanced when T 24 cells were treated for a longer time. Moreover, PARP proteins and pro-caspase 3, Bcl-2 were significantly inhibited after cantharidin treatment in T 24 cells. Pretreatment with the caspase 3 inhibitor markedly inhibited cantharidin-induced cell death. Therefore, we suggested that cantharidin could induce apoptosis via active caspase 3 in T 24 cells. When T 24 cells were treated with cantharidin at a low dose, the cell cycle was arrested in the G(2)/M phase. Furthermore, p21(Cip1/Waf1) was enhanced, and cyclin A, B1 and cdk1 decreased. At a high dose (more 12.5 microM), cantharidin could stimulate T 24 cells to deplete a large number of ATP and induce secondary necrosis. In addition, cantharidin also stimulated COX 2 over-expression and PGE(2) production in T 24 cells, in a dose-dependent manner. However, cantharidin also induced apoptosis and G(2)/M phase arrest in HT 29 cells, but did not induce COX 2 over-expression. Therefore, we suggest that cantharidin may induce cystitis through secondary necrosis and COX 2 over-expression.
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Affiliation(s)
- Steven Kuan-Hua Huan
- .Division of Urology, Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan, ROC
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23
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Romero G, Garrido JA, Rodríguez-Vázquez M, García-Arpa M, Cortina P, García-Bracamonte B. Tratamiento tópico con cantaridina de moluscos contagiosos. ACTAS DERMO-SIFILIOGRAFICAS 2004. [DOI: 10.1016/s0001-7310(04)76881-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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24
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Barr AC, Wigle WL, Flory W, Alldredge BE, Reagor JC. Cantharidin poisoning of emu chicks by ingestion of Pyrota insulata. J Vet Diagn Invest 1998; 10:77-9. [PMID: 9526864 DOI: 10.1177/104063879801000113] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- A C Barr
- Texas Veterinary Medical Diagnostic Laboratory, College Station 77841, USA
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25
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Karras DJ, Farrell SE, Harrigan RA, Henretig FM, Gealt L. Poisoning from "Spanish fly" (cantharidin). Am J Emerg Med 1996; 14:478-83. [PMID: 8765116 DOI: 10.1016/s0735-6757(96)90158-8] [Citation(s) in RCA: 87] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Cantharidin, known popularly as Spanish fly, has been used for millennia as a sexual stimulant. The chemical is derived from blister beetles and is notable for its vesicant properties. While most commonly available preparations of Spanish fly contain cantharidin in negligible amounts, if at all, the chemical is available illicitly in concentrations capable of causing severe toxicity. Symptoms of cantharidin poisoning include burning of the mouth, dysphagia, nausea, hematemesis, gross hematuria, and dysuria. Mucosal erosion and hemorrhage is seen in the upper gastrointestinal (GI) tract. Renal dysfunction is common and related to acute tubular necrosis and glomerular destruction. Priapism, seizures, and cardiac abnormalities are less commonly seen. We report four cases of cantharidin poisoning presenting to our emergency department with complaints of dysuria and dark urine. Three patients had abdominal pain, one had flank pain, and the one woman had vaginal bleeding. Three had hematuria and two had occult rectal bleeding. Low-grade disseminated intravascular coagulation, not previously associated with cantharidin poisoning, was noted in two patients. Management of cantharidin poisoning is supportive. Given the widespread availability of Spanish fly, its reputation as an aphrodisiac, and the fact that ingestion is frequently unwitting, cantharidin poisoning may be a more common cause of morbidity than is generally recognized. Cantharidin poisoning should be suspected in any patient presenting with unexplained hematuria or with GI hemorrhage associated with diffuse injury of the upper GI tract.
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Affiliation(s)
- D J Karras
- Division of Emergency Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
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26
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McCluskey A, Taylor C, Quinn RJ, Suganuma M, Fujiki H. Inhibition of protein phosphatase 2A by cantharidin analogues. Bioorg Med Chem Lett 1996. [DOI: 10.1016/0960-894x(96)00166-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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27
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Honkanen RE. Cantharidin, another natural toxin that inhibits the activity of serine/threonine protein phosphatases types 1 and 2A. FEBS Lett 1993; 330:283-6. [PMID: 8397101 DOI: 10.1016/0014-5793(93)80889-3] [Citation(s) in RCA: 221] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Cantharidin, a natural toxicant of blister beetles, is a strong inhibitor of protein phosphatases types 1 (PP1) and 2A (PP2A). Like okadaic acid, cantharidin inhibits the activity of the purified catalytic subunit of PP2A (IC50 = 0.16 microM) at a lower concentration than that of PP1 (IC50 = 1.7 microM) and only inhibits the activity of protein phosphatase type 2B (PP2B) at high concentrations. Dose-inhibition studies conducted with whole cell homogenates indicate that cantharidin also inhibits the native forms of these enzymes. Thus, cantharidin, which is economical and readily available, may be useful as an additional probe for studying the functions of serine/threonine protein phosphatases.
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Affiliation(s)
- R E Honkanen
- Department of Biochemistry, College of Medicine, University of South Alabama, Mobile 36688
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28
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Abstract
A case of fatal poisoning due to voluntary ingestion of cantharides powder for aphrodisiac purposes is reported. Clinical history, autopsy and analytical findings are described. Blood and urine samples collected during the 30 h of survival, as well as the cantharides product, were analyzed by gas chromatography-mass spectrometry. On the basis of the percentage of the active principle measured in the powder, an ingested dose of 26-45 mg of cantharidin could be estimated.
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Affiliation(s)
- A Polettini
- Chair of Forensic Toxicology, University of Pavia, Italy
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29
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Hundt HK, Steyn JM, Wagner L. Post-mortem serum concentration of cantharidin in a fatal case of cantharides poisoning. Hum Exp Toxicol 1990; 9:35-40. [PMID: 2328147 DOI: 10.1177/096032719000900108] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
A patient admitted to hospital died shortly after admission without a proper diagnosis having been made. Symptoms as well as the presence of a brown powder found in the possession of the deceased indicated the possibility of cantharidin intoxication. Cantharidin was positively identified by means of a GC/MS analysis, utilizing the selected ion monitoring technique (SIM), for m/z = 197.0813, (M + H+) for cantharidin, under positive chemical ionization conditions at a resolution of 7000 and a mass window of 30 ppm. Quantitation was done by means of a GC/MS SIM analysis of a toluene extract of acidified post-mortem serum under El+ conditions at a resolution of 3000, using clofibrate as internal standard and monitoring m/z = 128.0473 and 128.0029 for cantharidin and clofibrate respectively. The post-mortem serum was found to contain cantharidin at a concentration of 72.3 ng/ml whilst the cantharides powder contained 0.87% cantharidin.
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Affiliation(s)
- H K Hundt
- Department of Pharmacology, Medical Faculty, University of the Orange Free State, Bloemfontein, South Africa
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30
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Abstract
Cantharidin toxicosis in horses has become an increasing problem in certain regions of the United States. Toxicosis occurs when horses ingest alfalfa hay or products that are contaminated with "blister" beetles. Clinical signs may vary from depression to severe shock and death, depending upon the amount of toxin ingested. The most frequently observed signs include varying degrees of abdominal pain, anorexia, depression, and signs suggestive of oral irritation. Many horses make frequent attempts to void urine. Less commonly observed signs include synchronous diaphragmatic flutter and erosions of the oral mucosal surfaces. Clinical laboratory abnormalities suggestive of cantharidin toxicosis include persistent hypocalcemia and hypomagnesemia, development of hypoproteinemia, microscopic hematuria, and mild azotemia with inappropriate urine specific gravity. Chemical analysis for cantharidin is accomplished by evaluation of urine or stomach contents. Treatment of cantharidin toxicosis is symptomatic, but must include removal of toxin source. Gastrointestinal protectants, laxative, intravenous fluids, analgesics, diuretics, calcium gluconate, and magnesium are all included in the treatment regimen. Early and vigorous therapy is imperative if it is to be successful. In horses that remain alive for several days, persistence of elevated heart and respiratory rates and increasing serum creatine kinase concentration are associated with a deteriorating condition. Prevention is aimed at timely harvesting of alfalfa hay. Hay fields should be inspected for the presence of beetle clusters before harvesting. Involved areas of the field should not be harvested.
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Affiliation(s)
- D G Schmitz
- Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A&M University, College Station 77843
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31
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Affiliation(s)
- M McGuigan
- Division of Clinical Pharmacology/Toxicology, Hospital for Sick Children, Toronto, Ontario, Canada
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32
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Graziano MJ, Waterhouse AL, Casida JE. Cantharidin poisoning associated with specific binding site in liver. Biochem Biophys Res Commun 1987; 149:79-85. [PMID: 3689419 DOI: 10.1016/0006-291x(87)91607-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
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 in vivo 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.
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Affiliation(s)
- M J Graziano
- Department of Entomological Sciences, University of California, Berkeley 94720
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33
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Graziano MJ, Casida JE. Comparison of the acute toxicity of endothal and cantharidic acid on mouse liver in vivo. Toxicol Lett 1987; 37:143-8. [PMID: 2955551 DOI: 10.1016/0378-4274(87)90150-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Endothal and cantharidic acid were administered intraperitoneally to mice at 75 and 10 mg/kg, respectively, to compare their acute toxicity on liver tissue in vivo. Within 45 min both treatments caused extreme liver enlargement and congestion. Hepatic glycogenolysis was increased as evidenced by elevations in blood glucose and hepatic glycogen phosphorylase levels and by corresponding reductions in hepatic glycogen content and glycogen synthase activity. Endothal decreased hepatic ATP concentrations, although neither compound altered mitochondrial Mg2+-ATPase activity. Microsomal Mg2+-ATPase levels, however, were reduced by both treatments. There were no indications that reactive intermediates were involved in the toxicity of either compound. The results show that endothal and cantharidic acid act directly and cause similar biochemical changes in mouse liver in vivo.
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34
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Carrel JE, Doom JP, McCormick JP. Quantitative determination of cantharidin in biological materials using capillary gas chromatography with flame ionization detection. JOURNAL OF CHROMATOGRAPHY 1985; 342:411-5. [PMID: 4055965 DOI: 10.1016/s0378-4347(00)84536-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Spyker DA, Lynch C, Shabanowitz J, Sinn JA. Poisoning with 4-aminopyridine: report of three cases. Clin Toxicol (Phila) 1980; 16:487-97. [PMID: 6250762 DOI: 10.3109/15563658008989978] [Citation(s) in RCA: 91] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Four-aminopyridine is an acutely toxic avicide considered by the manufacturer to be a bird "repellant" because only a small number of birds are acutely poisoned, become disoriented, and emit a distress cry frightening other members of the flock. Four-aminopyridine dramatically enhances transmission at the neuromuscular junction and other synapses, and has been employed clinically in the treatment of prolonged paralysis caused by antibiotics and muscle relaxants, and in the Eaton-Lambert syndrome. In this paper we report the results of an acute poisoning misadventure in three adult males. We review the animal toxicology, summarize the neurophysiological research using 4-AP as a potassium channel blocker, comment on clinical applications, and outline the management of overdose with this agent.
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Friesen JM, Ferris JA, Rabkin SS, Fung HY. Pathological features of cantharidin-induced toxic cardiomyopathy: lack of correlation between electron-microscopic and histopathologic myocardial damage. Forensic Sci Int 1979; 13:187-92. [PMID: 88399 DOI: 10.1016/0379-0738(79)90287-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Electron-microscopic evidence of the cardiotoxic effects of cantharidin administered to rabbits was observed. No correlation was found between the electron-microscopic changes and the light-microscopic features as assessed by special histological stains. The reasons for this are discussed.
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Abstract
Case records of 21 horses that had acute illness after eating baled alfalfa hay containing dead striped blister beetles were reviewed. Tissue sections from 14 of the horses were examined; sections from two normal horses and several others with unrelated diseases were used for comparison.Clinical illness was characterized by abdominal pain, fever, depression, frequent urination, shock and, occasionally, synchronous diaphragmatic flutter. Laboratory findings were hemoconcentration, neutrophilic leukocytosis, hypocalcemia, hematuria and low urine specific gravity. Major morphologic changes were sloughing of the stratified squamous epithelium of the stomach, hemorrhage and ulceration in the urinary bladder, enterocolitis and myocardial necrosis. Five horses with experimental poisoning had lesions and clinical signs similar to those of the natural disease.Acute disturbance of both the gastrointestinal and urinary tracts, and the stomach and bladder lesions, were regarded as sufficiently suggestive of blister beetle poisoning to be useful in differential diagnosis, but no pathognomonic lesions were found. Therefore, striped blister beetles should be sought in hay fed to affected horses if blister beetle poisoning is suspected.
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38
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Abstract
Cantharidin, the well-known terpenoid compound from the blood of blister beetles (and active principle of Spanish fly), is a feeding deterrent to insects, effective at a concentration of 10(-5) molar.
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40
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STOUGHTON RB, BAGATELL F. The Nature of Cantharidin Acantholysis11From the Western Reserve University, Cleveland, Ohio. J Invest Dermatol 1959; 33:287-92. [PMID: 13835014 DOI: 10.1038/jid.1959.152] [Citation(s) in RCA: 55] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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41
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Intoxikationsf�lle durch das Pulver der spanischen Fliege, beziehungsweise durch Cantharidin. Arch Toxicol 1958. [DOI: 10.1007/bf00577614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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42
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CSIKY P. [Intoxications by the powder of the Spanish fly, especially by cantharidin]. ARCHIV FUR TOXIKOLOGIE 1958; 17:27-31. [PMID: 13534625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
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