Research Progress on Multiple Organ Damage and Mechanism of Cantharidin Poisoning / 法医学杂志

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.

Cantharidin suppressed breast cancer MDA-MB-231 cell growth and migration by inhibiting MAPK signaling pathway

As an active constituent of the beetle Mylabris used in traditional Chinese medicine, cantharidin is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays a crucial role in cell cycle progression, apoptosis, and cell fate. The role and possible mechanisms exerted by cantharidin in cell growth and metastasis of breast cancer were investigated in this study. Cantharidin was found to inhibit cell viability and clonogenic potential in a time- and dose-dependent manner. Cell cycle analysis revealed that cell percentage in G2/M phase decreased, whereas cells in S and G1 phases progressively accumulated with the increasing doses of cantharidin treatment. In a xenograft model of breast cancer, cantharidin inhibited tumor growth in a dose-dependent manner. Moreover, high doses of cantharidin treatment inhibited cell migration in wound and healing assay and downregulated protein levels of major matrix metalloproteinases (MMP)-2 and MMP-9. MDA-MB-231 cell migration and invasion were dose-dependently inhibited by cantharidin treatment. Interestingly, the members of the mitogen-activated protein kinase (MAPK) signaling family were less phosphorylated as the cantharidin dose increased. Cantharidin was hypothesized to exert its anticancer effect through the MAPK signaling pathway. The data of this study also highlighted the possibility of using PP2A as a therapeutic target for breast cancer treatment.

Combination of triptolide with sodium cantharidinate synergistically enhances apoptosis on hepatoma cell line 7721 / 中南大学学报(医学版)

OBJECTIVE@#To determine the combined cytotoxic effect and the molecular basis of triptolide and sodium cantharidinate on hepatoma cell line 7721.
@*METHODS@#After treating the hepatoma cell line 7721 with triptolide(9, 18, or 36 μg/mL) and/or sodium cantharidinate (2, 5, or 10 μg/mL), cell viability assay and apoptosis were examined by MTT and flocytometry, respectively. The protein levels of caspase 3 and nuclear factor κB were analyzed by Western blot.
@*RESULTS@#Viability of hepatoma cell line 7721 was inhibited by either the therapy of triptolide and/or sodium cantharidinate (P<0.05) in a time- and dose-dependent manner. The combined effects of both drugs were better than those of the single drug (P<0.05). The combined therapy down-regulated the expression of NF-κB p65 (P<0.05) while up-regulated the expression of caspase-3 (P<0.05).
@*CONCLUSION@#Triptolide and sodium cantharidinate exert a synergistic toxic effect on hepatoma cell line 7721, which is related to increasing capase-3 activity and suppression of NF- κB.

Inhibitory effect of compound cantharides capsule on the proliferation of xenografts of human hepatocellular carcinoma HepG(2)215 in mice / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the inhibitory effect of compound cantharides capsules on the proliferation of xenografts of human hepatocellular carcinoma HepG(2215) in mice and their mechanism of action.</p><p><b>METHODS</b>One hundred healthy Balb/c mice (5-week old, male:female 1:1) were used in this study. Mouse models of human HepG(2215) hepatocarcinoma were established. The tumor-bearing mice were divided into five groups randomly. The control group A received daily intragastric administration of physiologic saline. The intervention groups B1, B2 and B3 were treated with compound cantharides capsule in a dose of 12.5 mg×kg(-1)×d(-1), 25 mg×kg(-1)×d(-1) and 37.5 mg×kg(-1)×d(-1), respectively, for 10 consecutive days. The group C had intraperitoneal injection of cyclophosphamide (25 mg×kg(-1)×d(-1)) for 10 consecutive days. The mice were sacrificed after the completion of administration. The tumors were taken out, the tumor volume was measured, the inhibitory rate of body weight was calculated, and the serum AFP concentration and the level of HBV DNA were determined. The survival of each group mice was analyzed. The levels of mRNA expression of apoptosis-related genes were assayed by quantitative RT-PCR. Apoptosis in the tumor cells was assayed with TUNEL staining. Flow cytometry was used to detect the levels of CD3(+), CD19(+), CD4(+) and CD8(+), and microvessel density (MVD) of the tumors was assessed by immunohistochemistry.</p><p><b>RESULTS</b>After completion of the treatment, the inhibition rate of tumor growth of the groups B1, B2 and B3 was 29.8%, 38.7% and 48.1%, respectively, and that of the group C was 52.4%, with a significant difference among the groups (P < 0.05). The median survival time of the groups A, B1, B2, B3 and C was (30.0 ± 3.2) days, (49.0 ± 5.1) days, (50.0 ± 5.2) days, (57.5 ± 6.5) days and (49.0 ± 4.7) days, respectively. The median survival time of the group B3 was significantly longer than that of other groups (P < 0.05). The serum AFP level in the groups A, B1, B2, B3 and C was (492.7 ± 48.5) ng/ml, (281.2 ± 25.6) ng/ml, (194.3 ± 18.7) ng/ml, (170.1 ± 15.8) ng/ml and (138.7 ± 12.5) ng/ml, respectively, indicating that it was significantly inhibited in the group C. The inhibition rate of HBV DNA replication of the groups B1, B2, B3 and C was (46.0 ± 5.1)%, (65.5 ± 6.9)%, (81.3 ± 7.8)% and (19.5 ± 2.1)%, respectively, showing that compound cantharides capsules inhibited HBV DNA replication in a dose-dependent manner. The apoptosis rate of the groups A, B1, B2, B3 and C was (0.27 ± 0.03)%, (7.18 ± 2.12)%, (9.17 ± 2.42)%, (11.27 ± 3.03)% and (5.44 ± 2.45)%, respectively, and that of the group B3 was significantly higher than that of the groups A, B1, B2 and C (P < 0.05). The expression level of bax mRNA was significantly higher than that of the group C (P < 0.05). The drug could significantly decrease the bcl-2 mRNA expression level, more remarkably along with the increasing dose of cantharides, and it was significantly lower than that in the group C (P < 0.05). The levels of CD4(+), CD8(+), CD3(+) and CD19(+) were significantly higher than that in the groups A and C (P < 0.05). The value of MVD of the group B3 was significantly lower that that of groups A and C (P < 0.05).</p><p><b>CONCLUSION</b>Compound cantharides capsules may inhibit the replication of HBV DNA in HepG(2215) cells, inducing apoptosis in the tumor cells, enhancing the immune function to inhibit the growth of liver cancer cells in mice, and significantly prolong the median survival time of tumor-bearing mice.</p>

Origin, transfer and distribution of cantharidin-related compounds in the blister beetle Hycleus scabiosae

Cantharidin provides chemical protection for the coleopteran families Meloidae and Oedemeridae. In the present study, it was observed that cantharidin concentration in Hycleus scabiosae was slightly decreased from mated females (mean = 0.011 mg/mg of dry weight) to males (mean = 0.010 mg/mg) and considerably diminished in relation to virgin females (mean = 0.005 mg/mg). Significant concentrations of palasonin (21.69 ng/mg among virgins and 17.49 ng/mg in mated females) and palasoninimide (14.62 ng/mg in virgins and 9.17 ng/mg in mated females) were found in H. scabiosae. Palasonin, palasoninimide and cantharidinimide content of eggs were measured as 5.61, 7.69 and 7.80 ng/mg respectively. Surprisingly, males showed no trace of cantharidin-related compounds (CRCs); therefore CRCs in H. scabiosae could not be transferred from males to females and based on experiments employing its deuterated form, cantharidin is probably independently synthesized in females from the male nuptial transfer. An inseminated female incorporates about 38.5 ng of cantharidin (0.34 percent of the maternal content), 196.35 ng of palasonin (91.82 percent of maternal content) and 269.15 ng of palasoninimide (96.70 percent maternal content) into each egg mass during oviposition. It seems that eggs of this meloid species exploit a different array of protective chemicals by increasing the ratio of CRCs versus cantharidin. CRCs are less toxic than cantharidin; therefore, such compounds might have been deposited in eggs as a safer substitute for cantharidin to provide effective protection, but does not simultaneously harm the susceptible embryo.(AU)

Determination of plasma concentration of N-methylcantharidimide by HPLC and its pharmacokinetics after intravenous administration in dogs / 中国中药杂志

<p><b>OBJECTIVES</b>To establish a HPLC method for determination of N-methylcantharidimide in dogs' plasma and to study the pharmacokinetics of N-methylcantharidimide in dogs'.</p><p><b>METHOD</b>The plasma samples were extracted by methanol. The acetonitrile and the purified water composed mobile phase. The flow rate was 0. 7 mL x min(-1), ultraviolet detection wavelength was at 212 nm.</p><p><b>RESULT</b>The calibration curve was linear over the range from 0.01-10.0 mg x L(-1) with a correlation coefficiency of 0.996 3. The lower limit of quantitation was 0.01 mg x L(-1). The mean recovery was 92.3%. the relative standard deviation (RSD) of intra-day and inter-day were all less than 10%. After intravenous administration of N-methylcantharidimide with 3 dosages of 10, 15, 20 mg x kg(-1) to dogs, the corresponding distribution half-livers (t1/2alpha) were 1.8, 2.1, 1.7 min, and the elimination half-lives (t1/2beta) were 144,139, 146 min, respectively.</p><p><b>CONCLUSION</b>This method is convenient, accurate and reliable. It can be used for determination of N-methylcantharidimide in dogs' plasma and pharmacokinetic studies.</p>

Preparation and characterization of non-ionic surfactant vesicle of cantharidin / 中国中药杂志

<p><b>OBJECTIVE</b>To study the preparation of cantharidin entrapped non-ionic surfactant vesicle (noisome)and evaluate its quality.</p><p><b>METHOD</b>The niosome loaded with cantharidin was prepared using injection method by non-ionic surfactants as the carrier. An centrifugation separation method and HPLC analysis method of the cantharidin were established to detect the entrapment efficiency. The optimum preparation technology was established by a orthogonal experiment. The morphology, and particle size were studied to evaluate the preparation.</p><p><b>RESULT</b>The average size of niosomes were (209. 8 +/- 0.5) nm. The entrapment efficiency of the CTD-NS was (27.5% +/- 2.0%) and Zeta potential was (41.5 +/- 0.65) mV.</p><p><b>CONCLUSION</b>The preparation of cantharidin noisome by TweenA and SpanB is practicable and successful. These experiments can be the basement of developing targeting drug delivery system.</p>

Pharmacokinetics and bioavailability of cantharidin in beagle dogs / 中国中药杂志

<p><b>OBJECTIVE</b>To study the pharmacokinetics and bioavailability of cantharidin in beagle dogs to evaluate the pharmacokinetic parameters and bioavailability of cantharidin in beagle dogs by determining dose-time curve and by comparing with the pharmacokinetics of cantharidin injection.</p><p><b>METHOD</b>Six beagle dogs, after protein precipitation by hydrochloric acid, ethyl acetate was applied to extract cantharidin from plasma The plasma concentration of cantharidin in beagle dogs was determined by GC-MS. The WinNonLin program was used to calculate the pharmacokinetic parameters and bioavailability.</p><p><b>RESULT</b>The main pharmacokinetic parameters of cantharidin by iv in dogs (34 mL x h(-1) x kg(-1)) were AUC (203.5 +/- 23.8) h x microg x L(-1), CL (168.8 +/- 18.6) mL x h(-1) x kg(-1), t1/2 (0.69 +/- 0.03) h. The main pharmacokinetic parameters of cantharidin by op (102 microg x kg(-1)) were: AUC (160.4 +/- 26.9) h x microg x L(-1), CL (649.1 +/- 97.7) mL x h(-1) x kg(-1), t1/2 (0.38 +/- 0.1) h., F (bioavailability) = 26.7% comparing to injection.</p><p><b>CONCLUSION</b>As compared with cantharidin injection, the absorption of catharidin by op is poor and the bioavailability is also low, indicating that enhancement of the bioavailability will be beneficial to the clinical application.</p>

Research progress on medicinal resources of Mylabris and close origin species / 中国中药杂志

The paper summarizes the research progress on the medicinal resources of Mylabris and close origin species in recent years. Besides the 45 species in 7 genus within Meloidae insects which contain cantharidin, there are also more 9 species in 7 close origin genus containing cantharidin which include Zanna, Fulgora and Lycorma within Fulgoridae of Homoptera, Oxocopis, Heliocis Xanthochroa and Oedemera within Oedemeridae of Coleoptera. New medicinal resources of cantharidin are redundant, there are biological relationships in the biosynthesis of cantharidin, the emerge of cantharidin is related to ecology and there is more attention on the new methods of utilizing Mylabris resources such as living body extraction.

Simón Bolívar y las cantáridas / Simon Bolivar and the cantharides

Simon Bolivar, The Liberator, did not trust medical care and if he ever requested a doctor, it seems to have been mainly politically motivated. Unfortunately his fears seem to have been correct as his death was accelerated by Dr. Revenand, a man whose medical title is yet under discussion, who applied an extract of cantharides, a beetle known as "the Spanish fly", employed generally as an aphrodisiac, over Bolivar's neck region. According to popular belief of the time, cantharidin, the insect's active principle, reduced "the excess of humours", such as cerebrospinal fluid, plasma, "pituita" and others. Cantharidin has severe adverse effects and was for sure the origin of great suffering for many unfortunate patients in the past.

Detection of cantharidin-related compounds in Mylabris impressa (Coleoptera: Meloidae)

Cantharidin is mainly found in the beetle families Meloidae and Oedemeridae (Insecta: Coleoptera) which are the natural producers of this terpene anhydride. Most studies to date have focused on cantharidin distribution in blister beetles, with few reports on recently found cantharidin-related compounds (CRCs). Using gas chromatography-mass spectrometry (GC-MS), the present work reported cantharidin and two CRCs, palasonin and cantharidinimide from Mylabris impressa stillata (Baudi, 1878) which was collected from Toyserkan county, Hamedan Province, Iran. Ionization provided mass spectra with characteristic fragments of cantharidin at m/z 96 and 128, demethylcantharidin at m/z 82 and 114, and cantharidinimide at m/z 70, 96 and 127. This is the first time that cantharidin and the two CRCs are found in the genus Mylabris which in turn is new to the field of venomous insects.(AU)

Apoptosis induced by cantharidin in human pulmonary carcinoma cells A549 and its molecular mechanisms / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the apoptosis-inducing effect of cantharidin in human lung cancer cells A549 and its molecular mechanisms.</p><p><b>METHODS</b>MTT assay was used to determine A549 cells proliferation. Light and electron microscopy, FACScan, Annexin V-FITC staining and DNA gel electrophoresis were used to detect apoptosis. The expression of bcl-2, Bax and survivin were examined by Western blot.</p><p><b>RESULTS</b>Cantharidin inhibited the proliferation of A549 cells. The cells treated with cantharidin showed a typical apoptotic morphology and hypodiploid peak before G(1) phase. Flow cytometry analysis with annexin quantitatively further confirmed the increase of cell apoptosis. DNA of treated A549 cells depicted a ladder pattern characteristic of apoptosis, indicating the presence of DNA fragmentation. Western blot assay showed that cantharidin increased the level of Bax expression and inhibited the level of bcl-2 and survivin expression.</p><p><b>CONCLUSION</b>Cantharidin can induce A549 cells apoptosis mainly via regulation of Bax, bcl-2 and survivin expression.</p>

In vitro anti-proliferation/cytotoxic activity of cantharidin (Spanish Fly) and related derivatives

The anti-cancer therapeutic promise of cantharidin is limited because of its high mammalian toxicity. In order to find new anti-cancer lead compounds with reduced toxicity of the cantharidin prototype, the following seven derivatives were screened against the human SH-SY5Y neuroblastoma and MCF-7 breast cancer cells in vitro: 2,3-dimethyl-7-oxabicylo-[2.2.1]heptane-2,3-dicarboxylic anhydride (cantharidin) [1], 1-cyclohexen-1,2-dicarboxylic anhydride [2], cis-4-cyclohexen-1,2-dicarboxylic anhydride [3], cis-1, 2-cyclohexanedicarboxylic anhydride [4], exo-7-oxabicyclo[2.2.1]hept-5-ene-2-3 dicarboxylic anhydride [5], exo-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride (norcantharidin) [6], and (S)-(-)-O-acetylmalic anhydride [7]. Cantharidin, was found to be the most effective anti-proliferative compound on both cell lines. However, on the human neuroblastoma cells cantharidin was of equal toxicity to compound [6]. Mode of action studies revealed that cantharidin inhibited growth factor-mediated activation of mitogen activated protein kinase (MAPkinase) and attenuated the de-phosphorylation of the extracellular regulated kinases 1 and 2 (erk1 and erk2)

Uso de cantaridina en verrugas comunes y moluscos contagiosos: un estudio abierto / Use of cantaridine in common warts and contagious mollusca: an open study

Se realiza un estudio abierto, no randomizado, para evaluar la respuesta de cataridina en pacientes con verrugas comunes y pacientes con muluscos contagiosos. Se concluye que la cantaridina es eficaz y segura en el tratamiento de moluscos contagiosos, no así en el caso de verrugas comunes, en que logramos una respuesta pobre

Analysis of pilocarpine, quinine and cantharidin in cosmetic hair lotions

Pilocarpine, quinine and cantharidin were qualitatively and quantitatively determined in three cosmetic hair lotions. The pharmacopeal tests, microcrystalization and TLC investigation revealed the presence of pilocarpine and cantharidin in all lotions, and quinine in Tonoscalpine and Healthy Hair lotions, only. Tonoscalpin contained 0.01% w/w of pilocarpine, 0.1% w/w of quinine and 0.056% w/w of cantharidin, while Dorin contained 0.97% w/w of pilocarpine, 0.048% w/w of cantharidin and was devoid of quinine, as determined by HPLC and acid-base titration methods. The Healthy Hair preparation tested contained 0.0042% w/w of pilocarpine, 0.002% w/w of quinine and 0.0344% of cantharidin. The HPLC method was proved more sensitive, rapid and reliable. The recovery percentage for the titrimetric and HPLC methods ranged from 95 to 98% and 98 to 100.7%, respectively

Venenos animales / Animals poisons

Esta colaboración trata de explicar lo relativo de los conceptos manejados en relación a los venenos animales y su acción terapéutica homeopática a través de la dinamización hahnemanniana. Las diferencias entre su acción tóxica y patogenética; su justificación a través de los parágrafos 19, 20 y 110 del Organón de Hahnemann. El planteo que otros conceptos son posibles en ciencia y la sugerencia de tender a una epistemología homeopática

Dermatitis ampollar causada por la Epicauta flagellaria (Erichson) (Coleoptera : Meloidae) / Blister dermatitis caused by Epicauta flagellaria (Erichson) (Coleoptera : Meloidae) species

Este trabajo constituye el primer informe de dermatitis ampollar causada por coleópteros de la familia Meloidae en Panamá. Se describe un brote familiar de dermatitis ampollar causado por la especie Epicauta flegallaria (Erichson). En otros casos de dermatitis ampollar diagnosticados anteriormente en el Laboratorio Conmemorativo Gorgas, la especie que la causó fue E. isthmica Werner. Las lesiones ampollares se producen cuando la cantaridina, una toxina vesicante contenida en el cuerpo del coleóptero, es liberada y entra en contacto con la piel, al ser aplastado o frotado en ella. Las medidas terapéuticas y la prevención de esta enfermedad son indicadas

Eosinophil Leucocytes in Cantharidin Blisters of Patients with Various Dermatoss / 대한피부과학회지

The increase of the eosinophil leukocytes can be taken as a sign of an allergic reaction it might be a helpful means for obtaining information on the etiology of diseases, therefore, examinations for eosinophil leukocytes in Cantharidin blisters was undertaken in normals and with various skin disorders. 1. In 30 healthy suhjects, blister eontained 56.47+42.5/mm3 of eosinophil leucocytes, and 80% of them never exceeded 66/mm3 of eosinophil leucocytes. 2. The highest eosinophil leukocytes among the various dermatoses was seen contact dermatitis (93.07+40.3/mm3) and drug eruption (92.17+21.1/mm3), atopic dermatitis (75.37+41.0/mm3), and chronic urticaria (72.28+24.2/mm3) were followed in order. 3. The eosinophil leukocytes were slightly increased in psoriasis vulgaris (69.14+29.9/mm3) and herpes zoster (63.25+20.4/mm3). 4. The eosinophil leucocytes were markedly increased in the skin disorders of allergic nature and slightly in non-allergic skin disorders.

Topical Treatment of Verrucae and Molluscum Contagiosum with Cantharidin / 대한피부과학회지

The pathologic changes of verrucae and molluscum contagiosum are limitted chiefly to epidermis, therefore treatment with cantharidin which forms acantholytic bulla is successful. Canthrides is dried, powdered blister beetle, and cantharidin is its purified active ingredient. Its primary cutaneous effect is acantholysis and death of epidermal cells. For topical treatment, catharidin was prepared as a 0.9% solution in mixture of 50% of acetone, 25% of ether and 25% flexibIe collodion U.S.P. The therapeutic efficacy of cantharidin was excellent to eliminate the lesions of verrucae and molluscum contagiosum, showing the complete recovery of 114 out of 117 lesions of verrucae, and 520 out of 550 lesions of molluscum contagiosum with 1 to 3 topical applications. From the above results, it should be pointed out that cantharidin has the several advantages at clinical uses for the treatment of verrucae and molluscum contagiosum: 1 No residual scarring. 2. No pain. 3. Excellent therapeut!c efficacy.