Animal Venom for Medical Usage in Pharmacopuncture in Korean Medicine: Current Status and Clinical Implication.

Animal venoms, widespread throughout the world, are complex mixtures, the composition of which depends on the venom-producing species. The objective of this study was to contribute to the development of animal venom-based medicines by investigating the use of animal venom pharmacopuncture in Korean medicine (KM) institutions. We surveyed 256 public health centers from 1 through 31 October 2019 as guided by the Ministry of Health and Welfare (MoHW). A questionnaire developed by an expert group was distributed and collected for statistical analysis. The survey identified three types of animal venom-based pharmacopuncture: bee, snake, and toad venoms. The medications are based on a single animal venom ingredient and produced in 11 external herbal dispensaries (EHDs). Each animal venom is processed, refined, and freeze-dried in a cleanroom to produce a powder formulation that is later measured, diluted, filtered, filled, sealed, sterilized, and packaged as pharmacopuncture injections used in KM institutions. Bee venom therapy is effective in treating musculoskeletal pain, snake venom therapy is effective in controlling bleeding during surgery, and toad venom therapy is effective in cancer treatment. The study suggests that bee, snake, and toad venoms could be used in medical institutions and have the potential for drug development.

Hiponatremia grave por ritual de purificación con veneno de rana amazónica (Kambô) / Severe hyponatremia after a purification ritual using an Amazonian frog poison (Kambô)

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Acquired short QT syndrome in a cancer patient treated with Toad.

Although drug-induced short QT syndrome (SQTS) has been recognized, we currently report the first acquired SQTS case induced by bufotalinin (toad, an antineoplastic drug), which is a traditional Chinese folk prescription. It has cross reaction with digoxin and affects the Na+ -K+ -ATPase, the SR Ca2+ release from ryanodine receptor-2 (RyR2), the reactive oxygen species (ROS) production from the mitochondria. The case presented with bradycardia, extreme QT shortening, and sinoatrial block that were resolved after gastric lavage, rehydration, electrolyte (hyperkalemia, hyponatremia, hypocalcemia) correction, and atropine injection. Clinicians should recognize a potential association between toad poisoning and SQTS from this case.

The syndrome of inappropriate antidiuretic hormone secretion after giant leaf frog (Phyllomedusa bicolor) venom exposure.

INTRODUCTION: In Europe body purification and natural balance restoring rituals are becoming increasingly popular, but an introduction of Amazonian shamanic rituals in urban Europe can result in unexpected adverse events. CASE REPORT: A 44-year-old woman attended a Kambô or Sapo ritual in Slovenia where dried skin secretion from a giant leaf frog (Phyllomedusa bicolor) was applied to five freshly burned wounds at her shoulder. Afterwards, she drank 6 litres of water and gradually developed nausea and vomiting, confusion, lethargy, muscle weakness, spasms and cramps, seizure, decreased consciousness level and short-term memory loss. The initial laboratory tests showed profound plasma hypoosmolality (251 mOsm/kg) proportional to hyponatremia (116 mmol/L) combined with inappropriately elevated urine osmolality (523 mOsm/kg) and high urine sodium concentration (87 mmol/L) indicating a syndrome of inappropriate antidiuretic hormone secretion. The patient was treated with 0.9% sodium chloride and a restriction of water intake. Plasma osmolality and hyponatremia improved one day after venom exposure, but the symptoms disappeared as late as the third day. CONCLUSION: In patients presenting with neurological symptoms and a line of small body burns Phyllomedusa bicolor venom exposure should be suspected. Acute symptomatic hyponatremia after Phyllomedusa bicolor venom exposure is the result of inappropriate antidiuretic hormone secretion that can be exacerbated by excessive water intake.

A meta-analysis of Cinobufacini combined with transcatheterarterial chemoembolization in the treatment of advanced hepatocellular carcinoma.

OBJECTIVE: The aim of this meta-analysis is to evaluate the clinical efficacy of cinobufacini combined with transcatheter arterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma. MATERIALS AND METHODS: By searching Medline, the Cochrane central register of controlled trials, EMBSE, ESMO, Wanfang and Chinese National Knowledge Infrastructure (CNKI) databases, the open published clinical trials compared the clinical efficacy of cinobufacini plus TACE versus TACE only in patients with advanced hepatocellular carcinoma were collected. The pooled objective response rate (ORR) and 1 or 2 year survival rate were calculated by Stata11.0 statistical software. RESULTS: Nine studies including a total of 659 subjects (333 in cinobufacini plus TACE and 326 in TACE only) were finally included in this meta-analysis. The pooled analysis demonstrated that cinobufacini plus TACE can significant increase the objective response rate (ORR) compared with TACE only with an relative risk of 1.28 (P = 0.006); The 1-year survival rate in cinobufacini plus TACE group was not significant difference compared with TACE only by pooling the data (RR = 1.24, P = 0.13); But the 2-year survival rate in cinobufacini plus TACE group was much higher than that of TACE only group with an RR of 2.0, (P = 0.001). CONCLUSION: This meta-analysis demonstrated that cinobufacini combined with TACE can significantly increase the objective response rate and 2-year survival rate compared with TACE only in patients with advanced hepatocellular carcinoma.

Bufotenine is able to block rabies virus infection in BHK-21 cells

Background Rabies is a fatal zoonotic neglected disease that occurs in more than 150 countries, and kills more than 55.000 people every year. It is caused by an enveloped single stranded RNA virus that affects the central nervous system, through an infection initiated by the muscular nicotinic acetylcholine receptor, according to many authors. Alkaloids, such as acetylcholine, are widespread molecules in nature. They are present in numerous biological fluids, including the skin secretion of many amphibians, in which they act (together with proteins, peptides and steroids) as protection agents against predators and/or microorganisms. Among those amphibians that are rich in alkaloids, there is the genus Rhinella.Methods Bufotenine was isolated from Rhinela jimi skin secretion after a liquid-liquid partition (H2O:CH2Cl2) and reversed phase high-performance liquid chromatography analyses (RP-HPLC). Bufotenine was also extracted from seeds of Anadenanthera colubrina in acetone solution and purified by RP-HPLC, as well. Structural characterization was performed by mass spectrometry and nuclear magnetic resonance analyses. Cytotoxic tests of bufotenine were performed over baby hamster kidney (BHK-21) cells using MTT test. For the antiviral activity,Rabies virus strain Pasteur vaccine (PV) was used on fluorescence inhibition test and fluorescent foci inhibition test, with both simultaneous and time course treatment of the cells with the virus and bufotenine.Results In the present work we describe the effects of bufotenine, obtained either from toads or plants, that can inhibit the penetration of rabies virus in mammalian cells through an apparent competitive mechanism by the nicotinic acetylcholine receptor. Moreover, this inhibition was dose- and time-dependent, pointing out to a specific mechanism of action...

Efficacy and safety of Huachansu combined with chemotherapy in advanced gastric cancer: a meta-analysis.

BACKGROUND: Huachansu, a Chinese medicine that comes from dried toad venom from the skin glands of Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider, has been used in treatment of cancers. We conducted a meta-analysis to evaluate the efficacy and safety of Huachansu combined with chemotherapy for advanced gastric cancer. METHODS: The main efficacy measures were total response rates, quality of life and one-year survival rate. We also assessed the safety of treatments by evaluating the rate of occurrence of gastrointestinal side effects, leucocytopenia and neurotoxicity. The pooled relative ratio (RR) with 95% confidence interval (95% CI) was calculated to estimate the efficacy and safety of Huachansu combined with chemotherapy. RESULTS: Fifteen randomized controlled trails were eligible. The result showed that Huachansu combined with chemotherapy was superior to simple chemotherapy treatment in increasing of total response rate [RR = 1.28; 95% CI: (1.11, 1.18)] and Karnofsky score [RR = 1.31; 95% CI: (1.18, 1.45)], and reducing gastrointestinal side effects [RR = 0.71; 95% CI: (0.61, 0.82)], and leucocytopenia [RR = 0.75; 95% CI: (0.64, 0.87)]; there was no significant difference on one-year survival rate (RR = 1.25; 95% CI: 0.73, 2.14) between combination group and simple chemotherapy group. CONCLUSION: Compared with chemotherapy control group, Huchansu combined with chemotherapy provide benefits for advanced gastric cancer on improving the response rate, increasing Karnofsky score, reducing leucocytopenia and major side effects such as gastrointestinal side effects caused by chemotherapy.

[Experimental study of suspicious sensitization component screening on Huachansu injection].

OBJECTIVE: To explore a new experimental method for screening of allergens in post-market traditional Chinese medicine injections by confirming allergens in Huachansu injection. METHOD: First of all, the serum of patients allergic to Huachansu injection were collected, at the same time, the dubious allergen was conjugated to bovine serum albumin (BSA) by EDC coupling procedure to form complete antigen (BNP-BSA), which makes it possible to reproduce the allergic reaction of Huachansu injection in vitro. The histamine liberation ratio, the level of TNF-alpha and Histamine released from RBL-2H3 mast cell were detected; the above data were compared with those obtained in vivo. RESULT: The difference of the histamine liberation ratio, the levels of TNF-alpha and histamine of the resibufogenin-BSA group, group of patients allergic to Huachansu injection were not significant compared with those of normal control group. However, there were significant difference in those data among the cinobufagin-BSA group, the blank control and normal control group (P<0.05). CONCLUSION: The allergen in the serum collected from patients allergic to Huachansu injection is resibufogenin.

Pilot study of huachansu in patients with hepatocellular carcinoma, nonsmall-cell lung cancer, or pancreatic cancer.

BACKGROUND: Huachansu, a Chinese medicine that comes from dried toad venom from the skin glands of Bufo gargarizans or B. melanostictus, has been used in the treatment of various cancers in China. The authors conducted a pilot study, using a phase 1 trial design, of huachansu in patients with advanced cancer. METHODS: Huachansu was administered intravenously for 14 days followed by 7 days off (1 cycle). Without significant adverse events or progressive disease, treatment continued beyond 2 cycles. The dose of huachansu was escalated as follows with 3 patients per cohort: 10 (level 1), 20 (level 2), 40 (level 3), 60 (level 4), and 90 (level 5) mL/m(2). RESULTS: Fifteen patients (hepatocellular cancer, n = 11; nonsmall cell lung cancer, n = 2; pancreatic cancer, n = 2) were enrolled in the trial, and no dose-limiting toxicities (DLTs) were found. Eleven patients had no drug-related toxicity greater than grade 1. Six (40%) had stable disease (median duration, 6.0 months; range, 3.5-11.1 months). One of these patients (with hepatocellular cancer) had 20% regression (duration, 11 months) (dose level 1). Quality of life improved for patients with stable disease. Plasma bufalin concentration reached maximal levels at the end of the 2-hour infusion and was proportional to the amount of drug being administered (0.81-3.38 ng/mL). CONCLUSIONS: No DLT was observed with the use of huachansu at doses up to 8x higher than typically used in China. Six patients had prolonged stable disease or minor tumor shrinkage.

Dosagem de marcadores cardíacos CK-MB e TnIc e eletrólitos no envenenamento experimental por veneno de sapo em cães / Determination of cardiac markers and CK-MB TnIc and electrolyte in experimental poisoning by poison frog in dogs

Dentre os sinais sistêmicos causados pelo envenenamento por veneno de sapo (bufotoxina) em cães, os efeitos cardiotóxicos são um dos mais importantes. O objetivo deste estudo foi avaliar as potenciais alterações no músculo cardíaco de cães envenenados experimentalmente por veneno de sapo e observar as alterações eletrolíticas que podem ocorrer nesse tipo de envenenamento. Utilizaram-se 20 cães divididos em grupo controle (n=5) e grupo envenenado (n=15). O veneno de sapo foi extraído por meio de compressão manual das glândulas paratóides. Após anestesia geral, os cães do grupo controle receberam placebo (solução fisiológica) e os do grupo envenenado uma alíquota do veneno por sonda orogástrica. As colheitas de sangue para dosagem dos marcadores cardíacos foram realizadas seis e 24 horas após o envenenamento. As colheitas de sangue para dosagem dos eletrólitos foram realizadas antes e duas, quatro, seis e 12 horas após o envenenamento. A análise estatística empregada foi o teste não-paramétrico de Mann-Withney (P<0,05). Os cães envenenados por veneno de sapo apresentaram elevação dos níveis dos marcadores cardíacos CK-MB e TnIc, confirmando a cardiotoxicidade do veneno. Hipocalemia e hipocalcemia foram também observadas nos cães envenenados.

Among the systemic signs of toad venom (bufotoxin) poisoning in dogs, the cardiotoxic effects are one of the most important. Thus, the objective of this experiment was to evaluate potential changes in the cardiac muscle in dogs poisoned experimentally by toad venom and to observe the eletrolyte alterations which may occur in this condition. Twenty dogs divided into control group (n=5) and poisoned group (n=15) were utilized. The toad venom was extracted by manual compression of the paratoidic glands. After general anesthesia, dogs in the control group received placebo and dogs in the poisoned group received the venom by orogastric catheter. Samples for dosage were collected 6 hours and 24 hours after poisoning and 0, 2, 4, 6 and 12 hours after poisoning for electrolytes dosage. The Man-Withney test was used for statistical analysis (P<0.05). The poisoned dogs showed (saline) elevated levels of cardiac markers CK-MB and TnIc, confirming the cardiotoxic effect of the bufotoxin. Hypokalemia and hypocalcemia were also observed.

Ocular toxicity caused by toad venom.

PURPOSE: To report a case of ocular toxicity caused by toad venom. METHODS: Observational case report. RESULTS: A 31-year-old man came to our clinic complaining of burning pain, photophobia, and blurred vision in both eyes. He reported that an hour earlier he had been handling a toad (Bufo bufo). It ejected a liquid from its back that splashed on the patient's face and made him rub his eyes. Corrected visual acuity was 20/50 in the right eye and 20/40 in the left eye. Slit-lamp microscopy revealed mild chemosis and stromal corneal edema with Descemet folds in both eyes. Intraocular pressure (IOP) was 9 mm Hg in both eyes. Posterior segment examination was normal. Topical dexamethasone every 4 hours and cycloplegic 3 times a day were prescribed. Forty-eight hours later, corneal edema and conjunctival chemosis had resolved, and IOP was 18 mm Hg. CONCLUSIONS: Ocular toxicity secondary to toad venom may cause corneal edema and low IOP that resolve without specific treatment in a short period.

Anfíbios e répteis do Parque Nacional da Serra da Bodoquena, Mato Grosso do Sul, Brasil / Amphibians and reptiles of the Serra da Bodoquena National Park, Mato Grosso do Sul, central Brazil

O Estado de Mato Grosso do Sul situa-se na porção mediana da grande diagonal de formações abertas da América do Sul, uma região que abriga uma grande diversidade de anfíbios e répteis, sendo algumas endêmicas. Apesar de sua importância biogeográfica, essa diagonal tem sido pouco considerada em estudos com abrangência regional. Dentre os componentes fitofisionômicos que compõem essa região e cuja representatividade se faz presente no Estado, as matas estacionais deciduais são elementos marcantes na região da Serra da Bodoquena. Devido a peculiaridade desse ambiente, muitas áreas ainda necessitam de uma maior avaliação quanto à sua biodiversidade. Informações sobre a herpetofauna do Parque Nacional da Serra da Bodoquena são escassas e pontuais e sugerem uma semelhança com a fauna de cerrado. Este trabalho apresenta registros da herpetofauna do Parque Nacional da Serra da Bodoquena e regiões de entorno, abrangendo áreas em bom estado de conservação e locais com atividade agropecuária. As amostragens foram realizadas em dois períodos, contemplando as estações seca e chuvosa na região. O inventário consistiu em busca ativa limitada por tempo, além de registros oportunísticos. Informações sobre a riqueza de espécies da herpetofauna da Caatinga, Cerrado e Chaco foram compiladas da literatura e comparadas com aquela registrada no presente trabalho. Foram registradas 63 espécies, sendo 38 anfíbios e 25 répteis. Muitas das espécies estavam associadas a ambientes particulares, como matas de galeria e afloramentos rochosos. A maior similaridade da herpetofauna do Parque Nacional da Serra da Bodoquena deu-se com aquela encontrada no Cerrado, provavelmente porque a área está inserida nesse bioma. Considerando-se a diversidade de hábitats da área, provavelmente o número de espécies deverá aumentar com a realização de novos inventários na região. Agregar novas informações sobre a herpetofauna da Serra da Bodoquena é fundamental para o plano de manejo...

The State of Mato Grosso do Sul, central Brazil, is located in the center of the broad South American open-dry diagonal areas. This region harbors a great diversity of amphibians and reptiles, with some endemic species. Despite such biogeographical scenario, biodiversity of this region is poorly known at local scales. Dry forests are important physiognomies in Mato Grosso do Sul and represent an important landscape element at Serra da Bodoquena, resulting in local characteristics that require biodiversity surveys. There are few and punctual information on the herpetofauna from the Serra da Bodoquena National Park and they suggest a similarity with the Cerrado herpetofauna. The present study represents the first record of the herpetofauna from the Serra da Bodoquena National Park and adjacent areas. Samples were conducted in pristine and disturbed areas in two distinct climatic periods, covering both rainy and dry seasons, by means of active search limited by time as well as opportunistic records. Data on the herpetofauna of the Caatinga, Cerrado, and Chaco biomes were compiled and compared with the species sampled in the present study. We registered 63 species, including 38 amphibians and 25 reptiles. Several species were associated to particular habitats, such as gallery forests or rocky outcrops. The herpetofauna from the Serra da Bodoquena National Park showed a greater similarity with that of the Cerrado, probably because the area is inserted in this biome. Considering the habitat diversity found at Serra da Bodoquena, the number of species must increase with other surveys in the area. Natural history and ecological studies on amphibian and reptiles of the Serra da Bodoquena must be encouraged in order to contribute for the National Park management.

Ranas venenosas de Colombia / Poisonous frogs of Colombia

Colombia es uno de los países del mundo más rico en biodiversidad. Ocupa el primer lugar en Amphibia, tanto en número de especies como en toxicidad. La familia Dendrobatidae está representada por los géneros Phyllobates, Dendrobates, Epipedobates y Minyobates, todas ellas venenosas. La mayoría de las especies están distribuidas en el occidente colombiano y a lo largo del Pacífico.Palabras claves: Dendrobatidae, batrachotoxinas, histrionicotoxina, pumiliotoxina, epibatidina, lehmizidina.

[Cardiotoxicity of vertebrates venoms]. / Kardiotoksyczne dzialanie jadów kregowców.

Vertebrate species (fish, amphibians and reptiles) with cardiotoxic venoms properties are described in the paper. A regulatory problems related to breeding of venomous animals are also included.