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The snakebite fight

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Abstract

Snakes kill tens of thousands of people each year. But experts can't agree on how best to overcome a desperate shortage of antivenom.

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... Venomous snakes were estimated to strike over two and a half million people every year, causing more than 100,000 deaths mainly in tropical and sub-tropical areas of the world. About a fourfold larger number of envenomed patients develop permanent physical and psychological sequelae, with high social costs [1][2][3][4][5]. Envenomation exhibits heterogeneity in its clinical manifestations and is believed by experts to be under reported, also because it mainly occurs in parts of the world characterized by a limited accessibility to hospitals or other healthcare facilities [1][2][3][4][5][6][7]. ...
... About a fourfold larger number of envenomed patients develop permanent physical and psychological sequelae, with high social costs [1][2][3][4][5]. Envenomation exhibits heterogeneity in its clinical manifestations and is believed by experts to be under reported, also because it mainly occurs in parts of the world characterized by a limited accessibility to hospitals or other healthcare facilities [1][2][3][4][5][6][7]. ...
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Snake envenoming is a major, but neglected, tropical disease. Among venomous snakes, those inducing neurotoxicity such as kraits (Bungarus genus) cause a potentially lethal peripheral neuroparalysis with respiratory deficit in a large number of people each year. In order to prevent the development of a deadly respiratory paralysis, hospitalization with pulmonary ventilation and use of antivenoms are the primary therapies currently employed. However, hospitals are frequently out of reach for envenomated patients and there is a general consensus that additional, non-expensive treatments, deliverable even long after the snake bite, are needed. Traumatic or toxic degenerations of peripheral motor neurons cause a neuroparalysis that activates a pro-regenerative intercellular signaling program taking place at the neuromuscular junction (NMJ). We recently reported that the intercellular signaling axis melatonin-melatonin receptor 1 (MT1) plays a major role in the recovery of function of the NMJs after degeneration of motor axon terminals caused by massive Ca²⁺ influx. Here we show that the small chemical MT1 agonists: Ramelteon and Agomelatine, already licensed for the treatment of insomnia and depression, respectively, are strong promoters of the neuroregeneration after paralysis induced by krait venoms in mice, which is also Ca²⁺ mediated. The venom from a Bungarus species representative of the large class of neurotoxic snakes (including taipans, coral snakes, some Alpine vipers in addition to other kraits) was chosen. The functional recovery of the NMJ was demonstrated using electrophysiological, imaging and lung ventilation detection methods. According to the present results, we propose that Ramelteon and Agomelatine should be tested in human patients bitten by neurotoxic snakes acting presynaptically to promote their recovery of health. Noticeably, these drugs are commercially available, safe, non-expensive, have a long bench life and can be administered long after a snakebite even in places far away from health facilities.
... In order to provide an assessment platform and labelled data (including geographic information) for biodiversity and health research, we developed SnakeCLEF2020: Automatic Snake Species Documentation Challenge. To provide a valuation stage that may aid in the presentation of end-to-end AI-driven snake class identification firms, SnakeCLEF2020 was developed [4]. The number of deaths and incapacities attributable to snakebites might be significantly decreased with the aid of a robust and accurate AI-driven system used as a support tool for snake class identification. ...
... This initiative was designed to establish an evaluation platform accompanied by meticulously labelled data, including geographical information, fostering research in both biodiversity and health domains. The primary objective of SnakeCLEF2020 is to serve as an evaluative stage, supporting the development of end-to-end AI-driven systems for the recognition and classification of snake species [4]. ...
Article
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This novel approach in animal biology could revolutionize identifying endangered species, addressing the issue of misclassifying potentially harmful animals based solely on visual characteristics. Particularly impactful for farmers in agricultural fields, it aims to reduce the heightened risk of venomous animal attacks, ultimately improving safety. Due to a lack of accessible education, illiterate farmers are more susceptible to adopting superstitious beliefs, which tragically leads to fatal snakebites even when medical treatment is readily available. Furthermore, environmental factors can unexpectedly hold typically non‐threatening animals responsible for a large number of human deaths each year. However, the complexity of human recognition of these hazards has prompted the development of a novel design approach aimed at simplifying the process. Integration of the ResNet learning algorithm in conjunction with You Only Look Once (YOLOv5) within the framework is recommended to facilitate real‐time processing and improve accuracy. This combined approach not only speeds up animal recognition but also takes advantage of ResNet's deep learning capabilities. The first phase entails deploying YOLOv5 to detect the presence of snakes in the proposed study, achieving a remarkable 87% precision in snake detection thanks to the synergistic fusion of ResNet and YOLOv5.
... The frequency and mortality of snakebites pose a serious burden in the rural communities of poor and developing countries. Globally, venomous snakes bite more than 1 3 5 million people every year, resulting in about 400,000 amputations and more than 100,000 deaths (Arnold 2016). In Egypt, venomous animals cause about 10,000 envenomation and over 200 deaths annually (Kasturiratne et al. 2008). ...
... Incidence and mortality resulting from snakebites pose a serious burden in the rural communities of poor and developing countries (Arnold 2016). The present study is carried out to assess and compare the in vivo toxicity and pathophysiology effects of three medically important Egyptian snake venoms. ...
Article
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Snakebite envenomation is a serious medical problem in many developing tropical and subtropical countries. Envenomation is registered by the World Health Organization as a neglected tropical disease due to critical shortages in the production of antivenom. Envenomation causes more than 100,000 deaths annually. Snakebites result in several effects to include edema, blistering, hemorrhage, necrosis and respiratory paralysis. Antivenom is the preferred treatment for the systemic effects of snakebite envenomation, though these are often ineffective in neutralizing venom toxin-induced local tissue damage. To effectively treat snakebites, it is important to determine the lethal potency and pathophysiological effects induced by specific snake venoms. In the current study, we compared the lethality, and the hemorrhagic and dermonecrotic activities of venoms from three snakes in Egypt that are the primary causes of local tissue necrosis. Our data show that the intraperitoneal median lethal doses (LD50) for Cerastes cerastes, Echis carinatus and Naja nigricollis venoms are 0.946, 1.744 and 0.341 mg/kg mouse body weight, respectively. These results indicated that N. nigricollis venom is the most toxic and significantly accelerated the time of death compared to the other two venoms. However, no hematoma or associated edema appeared upon sub-plantar injection of N. nigricollis venom into the mice hind paw. Two hours following intradermal injection of C. cerastes and E. carinatus venoms, macroscopic analysis of the inner surface of mouse skin showed severe hemorrhagic lesions, whereas only insignificant hemorrhagic lesion appeared in mice injected with the highest dose of N. nigricollis venom. Furthermore, the minimum necrotic doses (MND) for the same venoms were 43.15, and 70.87 µg/mouse, or not observed in the case of N. nigricollis venom, respectively. These LD50 values and pathophysiological results can be used to guide development of antivenom against bites by these dangerous Egyptian snakes.
... Because India accounts for a major share of world snakebite totals, global snakebite totals may potentially be underestimated. Snakebite deaths in India should be reduced by community education, adequate medical staff training, and better delivery of antivenom, particularly in the 13 states with the highest occurrence [23,24]. ...
Article
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The spotlight of our discussion here is on developing a model for detecting snakes present in the agricultural fields using cameras and machine learning algorithms. The idea is to construct a machine learning model to identify the snakes, which will be trained on a vast set of images of snakes. These images will be carefully selected to include the snake patterns, skin color of different species of snakes (extraction of the unique features). This is done to train the model properly to identify different types of snakes that the farmer encounters in the fields. Most famers are unaware and have a need for a way to detect these snakes so that they can either avoid them or get rid of them. Hence, this system can be implemented to prevent thousands of deaths and can help famers alleviate the repercussions of snake bites. Mistakes in recognizing potentially harmful animal species based only on visual cues are major contributors to the high death toll from venomous animal attacks. Since they spend so much time in the fields, where rice and wheat are cultivated, farmers are at a higher risk of being bitten by a snake than the general population. Because of their ignorance, illiterate farmers are more inclined to believe in superstitions, which can lead to their untimely deaths from snakebites despite medical intervention. Animals that would normally pose no threat to humans are responsible for the deaths of thousands of people every year because of environmental factors. However, because it is hard for humans to recognize these dangers, a new design paradigm has been developed to make it simpler. Researchers in the field of animal biology can use it to search for endangered species. Predators may enter gardens and green areas like tea and coffee plantations. There is not yet a plan in place to implement automated sorting for discovering distinctions. By applying the suggested framework to photographs of potentially dangerous animals, several factors useful for studying animal organization may be easily identified. For the classifier to run in real-time, it is suggested that YOLO be utilized for double processing within the framework. Furthermore, the YOLO technique enables quick animal recognition in a similar fashion. First, the YOLO method will be used to determine whether a snake is present in the proposed work. Here, 87 percent precision is also reached in the detection of snakes.
... Snakebite envenoming is a major world-wide health problem present in five continents and affecting 1.8-2.7 million people each year with as many as 138,000 deaths, and at least 400,000 envenomed patients suffering from permanent physical and/or psychological sequelae. Snakebites occur mainly in tropical and sub-tropical areas of the world (WHO, 2017), frequently in poor and rural zones where advanced hospital care may not be rapidly available and, therefore, these numbers are likely to be underestimated (Kasturiratne et al., 2008;Cruz et al., 2009;Harrison et al., 2009;Arnold, 2016;Gutiérrez et al., 2017;WHO, 2017;Longbottom et al., 2018). ...
Article
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People bitten by Alpine vipers are usually treated with antivenom antisera to prevent the noxious consequences caused by the injected venom. However, this treatment suffers from a number of drawbacks and additional therapies are necessary. The venoms of Vipera ammodytes and of Vipera aspis are neurotoxic and cause muscle paralysis by inducing neurodegeneration of motor axon terminals because they contain a presynaptic acting sPLA2 neurotoxin. We have recently found that any type of damage to motor axons is followed by the expression and activation of the intercellular signaling axis consisting of the CXCR4 receptor present on the membrane of the axon stump and of its ligand, the chemokine CXCL12 released by activated terminal Schwann cells. We show here that also V. ammodytes and V. aspis venoms cause the expression of the CXCL12‐CXCR4 axis. We also show that a small molecule agonist of CXCR4, dubbed NUCC‐390, induces a rapid regeneration of the motor axon terminal with functional recovery of the neuromuscular junction. These findings qualify NUCC‐390 as a promising novel therapeutics capable of improving the recovery from the paralysis caused by the snakebite of the two neurotoxic Alpine vipers. image
... Because of the specificity of the resulting immunoglobulins towards the toxins present in the venoms used in manufacture, antivenoms typically have limited efficacy against envenoming by different snake species 6 . Consequently, distinct antivenom products are produced (>45 manufacturers worldwide) to treat envenoming by numerous snake species found in different parts of the world, resulting in a highly fragmented drug market, issues with affordability, and a lack of sustainability 7,8 . Other limitations with current antivenom include the following: (i) poor dose efficacy, as the majority (~80-90%) of their immunoglobulins do not bind venom toxins 1,9 , (ii) high incidences of adverse reactions due to the administration of large doses of foreign immunoglobulins 10 , (iii) the requirement for intravenous delivery in a healthcare facility, and (iv) reliance on cold chain transport and storage. ...
Article
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Snakebite is a medical emergency causing high mortality and morbidity in rural tropical communities that typically experience delayed access to unaffordable therapeutics. Viperid snakes are responsible for the majority of envenomings, but extensive interspecific variation in venom composition dictates that different antivenom treatments are used in different parts of the world, resulting in clinical and financial snakebite management challenges. Here, we show that a number of repurposed Phase 2-approved small molecules are capable of broadly neutralizing distinct viper venom bioactivities in vitro by inhibiting different enzymatic toxin families. Furthermore, using murine in vivo models of envenoming, we demonstrate that a single dose of a rationally-selected dual inhibitor combination consisting of marimastat and varespladib prevents murine lethality caused by venom from the most medically-important vipers of Africa, South Asia and Central America. Our findings support the translation of combinations of repurposed small molecule-based toxin inhibitors as broad-spectrum therapeutics for snakebite.
... The real burden of snake-bite is mostly reported from middle and low-income tropical countries in the form of a huge number of mortalities and morbidities, particularly in agriculture occupants. [1][2][3] India contributes maximum to the snake envenomation caused morbidity and mortality with approx 46,000 deaths and even more morbidities every year. 4,5 Epidemiological profile of snake-bite in Haryana suggests annually around thousand snake-bites admissions in hospitals. ...
Article
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Snake-bite is a well-known but fairly ignored medical problem in India. Lack of precise first aid knowledge for snake-bite is a substantial reason for its severe fatality in human beings. The present study is comprised of a pilot survey that assesses and evaluates the knowledge of people of different occupations (teachers, students, farmers, medical residents, and miscellaneous) about snakes and snake-bite management. The pilot survey was conducted through a well-structured open-ended questionnaire about experiences with snakes and snake-bites and first aid measures for accidental snake-bites. Proper knowledge of snakes and snake-bite management was either diminutive or absent in the majority of the subjects, especially amongst teachers. Even the medical professionals were not well acquainted with knowledge about snakes and snake-bite management. Only 13% knew about ‘big four’, 18% knew ‘dry bite’, and 21% of subjects knew about anti-snake venom (ASV) used in India. 39% of subjects knew about the whereabouts of traditional healer. Only 12% of subjects, mostly medical residents, knew of any bedside test for diagnosis of snake-bite, and 11% of respondents also knew of LD50 of Indian cobra. A well-timed first aid treatment is always decisive in the management of life-threatening snake-bite cases but the present survey has found that most of the study groups had inadequate and little misleading fundamental knowledge comprising regional snakes, first aid measures for accidental snake-bite, and welfare schemes for snake-bite victims. Therefore, the present study proposes to conduct more such appraisals and strengthening of education curricula on snake-bite that would surely inculcate an adequate level of primary skill in ignorant societies.
... Death resulting from snakebites poses a serious health problem in the rural communities of developing countries. Globally, more than 5 million snakebite envenomings happen every year, resulting in about 400,000 amputations and more than 100,000 deaths [122]. At the end of the nineteenth century, snake antivenoms were first developed by Calmette using horses as a host for production [123]. ...
Article
Snake venoms are complex chemical mixtures of biologically active proteins and non-protein components. Toxins have a wide range of targets and effects to include ion channels and membrane receptors, and platelet aggregation and platelet plug formation. Toxins target these effectors and effects at high affinity and selectivity. From a pharmacological perspective, snake venom compounds are a valuable resource for drug discovery and development. However, a major challenge to drug discovery using snake venoms is isolating and analyzing the bioactive proteins and peptides in these complex mixtures. Getting molecular information from complex mixtures such as snake venoms requires proteomic analyses, generally combined with transcriptomic analyses of venom glands. The present review summarizes current knowledge and highlights important recent advances in venomics with special emphasis on contemporary separation techniques and bioinformatics that have begun to elaborate the complexity of snake venoms. Several analytical techniques such as two-dimensional gel electrophoresis, RP-HPLC, size exclusion chromatography, ion exchange chromatography, MALDI-TOF-MS, and LC-ESI-QTOF-MS have been employed in this regard. The improvement of separation approaches such as multidimensional-HPLC, 2D-electrophoresis coupled to soft-ionization (MALDI and ESI) mass spectrometry has been critical to obtain an accurate picture of the startling complexity of venoms. In the case of bioinformatics, a variety of software tools such as PEAKS also has been used successfully. Such information gleaned from venomics is important to both predicting and resolving the biological activity of the active components of venoms, which in turn is key for the development of new drugs based on these venom components.
... A certain degree of protection from venoms by suramin was confirmed in mouse models (77)(78)(79). The potential use of suramin as an antidote is attractive, given the high global burden of snakebites (80) and the current shortage of antivenom (81). ...
Article
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Suramin is a hundred years old and still being used to treat the first stage of acute human sleeping sickness, caused by Trypanosoma brucei rhodesiense . Suramin is a multifunctional molecule with a wide array of potential applications, from parasitic and viral diseases to cancer, snakebite and autism. Suramin is also an enigmatic molecule: What are its targets? And how does it get into cells in the first place? Here we provide an overview on the many different candidate targets of suramin, discuss modes of action, and routes of cellular uptake. We reason that once the polypharmacology of suramin is understood at the molecular level, new, more specific, and less toxic molecules can be identified for the numerous potential applications of suramin.
... Snakes undoubtedly represent the best-studied venomous animal group, mainly because snakebites kill at least 100.000 people per year and represent a WHO listed high priority neglected disease (Arnold, 2016;Chippaux, 2017;Gutiérrez et al., 2017;Williams et al., 2019). The production of an effective antidote is largely dependent on the present knowledge of a species' venom cocktail and possible intra-specific variation in its toxin components (Chippaux et al., 1991;Gutiérrez et al., 2009). ...
Article
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Venoms evolved convergently in diverse animal lineages as key adaptations that increase the evolutionary fitness of species which are manifold employed for defense, predation, and competition. They constitute complex cocktails of various toxins that feature a broad range of bioactivities. The majority of described venom proteins belong to protein families that are known to comprise housekeeping genes or harbor protein-domains, which are present in genes with non-venom related functions. However, the evolutionary processes and mechanisms that foster the origin of these venom proteins and triggered their recruitment into the venom delivery system are still critically discussed. In most instances single or combined proteomic and transcriptomic approaches are applied to describe venom compositions and the biological context of venoms. For neglected species these studies represent crucial contributions to improve our understanding of venom diversity on a broader scale. Nonetheless, the inference of the evolutionary origin of putative toxins in these studies could be misleading without appropriate coverage of gene populations from different tissue samples (gene completeness) or complementary genome data. Providing a valid backbone to correctly map transcriptome and proteome data, whole genome sequences facilitate a clear distinction between variability of venom proteins or toxins due to posttranslational modifications, alternative splicing, and false-positive matches that stem from sequencing or read processing and assembly errors. High-quality whole genome sequence data of venomous species are still sparse and unevenly distributed within taxon lineages. However, to reveal the evolutionary pattern of putative toxins in venomous lineages and to identify ancestral variants of venom proteins, the appropriate sampling of genomes from venomous and non-venomous species is crucial. Nevertheless, larger comparative studies based on multiple whole genome data sets are still sparse to uncover processes of venom evolution. Here, we review the general potential of comparative genomics in venomics to unravel mechanisms and patterns of evolutionary origin of toxin genes. Finally, we discuss the benefit of whole genome data to improve transcriptomics and proteomics-only studies, in particular if datasets are applied to assess the evolutionary origin of venom proteins.
... The high manufacturing cost and limited market potential made antivenom production unprofitable and not favored by the pharmaceutical industry (Chippaux and Habib, 2015;Gutiérrez et al., 2014). This leads to a serious shortage of antivenom supply in many parts of the world (Arnold, 2016;Chippaux, 2009), undermining the global effort in solving the world crisis of snakebite envenomation (Brown, 2012;Chippaux and Habib, 2015). ...
Article
Gel filtration chromatography and gel electrophoresis revealed minimal protein degradation in lyophilized antivenoms which were 2-year expired (Hemato Polyvalent, Neuro Polyvalent; Thailand) and 18-year expired (Hemato Bivalent, Neuro Bivalent; Taiwan). All expired antivenoms retained immunological binding activity, and were able to neutralize the hemotoxic or neurotoxic as well as lethal effects of the homologous snake venoms. The findings show that antivenoms under proper storage conditions may remain relatively stable beyond the indicated shelf life.
... Snakebite is still a worldwide health problem and according to the World Health Organization (WHO), around 5.4 million people are bitten by snakes, resulting in 400,000 amputations and more than 125,000 deaths each year [1,2]. Snakes from the genera Bothrops, Lachesis, Crotalus and Micrurus are responsible for the majority of envenomation cases in Brazil [3]. ...
Article
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Envenomation by the bushmaster snake Lachesis muta muta is considered severe, characterized by local effects including necrosis, the main cause of permanent disability. However, cellular mechanisms related to cell death and tissue destruction, triggered by snake venoms, are poorly explored. The purpose of this study was to investigate the cytotoxic effect caused by L. m. muta venom in normal human keratinocytes and to identify the cellular processes involved in in cellulo envenomation. In order to investigate venom effect on different cell types, Alamar Blue assay was performed to quantify levels of cellular metabolism as a readout of cell viability. Apoptosis, necrosis and changes in mitochondrial membrane potential were evaluated by flow cytometry, while induction of autophagy was assessed by expression of GFP-LC3 and analyzed using fluorescence microscopy. The cytotoxic potential of the venom is shown by reduced cell viability in a concentration-dependent manner. It was also observed the sequential appearance of cells undergoing autophagy (by 6 hours), apoptosis and necrosis (12 and 24 hours). Morphologically, incubation with L. m. muta venom led to a significant cellular retraction and formation of cellular aggregates. These results indicate that L. m. muta venom is cytotoxic to normal human keratinocytes and other cell lines, and this toxicity involves the integration of distinct modes of cell death. Autophagy as a cell death mechanism, in addition to apoptosis and necrosis, can help to unravel cellular pathways and mechanisms triggered by the venom. Understanding the mechanisms that underlie cellular damage and tissue destruction will be useful in the development of alternative therapies against snakebites.
... Los accidentes ofídicos continúan siendo un problema de salud pública, especialmente en países tropicales 1,2 . La Organización Mundial de la Salud estima que anualmente 5 millones de personas sufren mordeduras por serpientes, de ellas más de 100.000 mueren y hasta 400.000 sufren amputaciones 3 . En Colombia, el Instituto Nacional de Salud (INS) reportó que durante el 2016 se presentaron 4636 casos de accidente ofídico (con una tendencia creciente en comparación con años anteriores); en los cuales se informaron 31 defunciones, 16 no fueron hospitalizadas y en los 15 decesos adicionales no se suministró suero antiofídico 4 . ...
Article
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Introduction: Snakebites continue to be a public health problem, especially in tropical countries like Colombia. Objetive: To characterize the snakebite cases attended by a new poison center in Medellin, Colombia. Methodology: A descriptive, retrospective study was carried out, reviewing the information of the Center’s database from January 1st to December 31st, 2016. Results: There were 117 cases of ophidian accidents, affecting 93 men (79%) and 24 women (21%), with a median age of 32 years (range: 2 to 82 years). The follow-up of the cases could be done in 55 of the 117 accidents (47%), and complications were described in 18 of those 55 (33%) patients. The most commonly reported complication was a pruritic maculopapular rash that was associated to serum administration, without differences between the several brands of anti-ophidian serum used. The death of one patient (0.85%) was documented. The genus Bothrops caused most of the accidents. Discussion: Our results agree with previously published data.
... Los accidentes ofídicos continúan siendo un problema de salud pública, especialmente en países tropicales 1,2 . La Organización Mundial de la Salud estima que anualmente 5 millones de personas sufren mordeduras por serpientes, de ellas más de 100.000 mueren y hasta 400.000 sufren amputaciones 3 . En Colombia, el Instituto Nacional de Salud (INS) reportó que durante el 2016 se presentaron 4636 casos de accidente ofídico (con una tendencia creciente en comparación con años anteriores); en los cuales se informaron 31 defunciones, 16 no fueron hospitalizadas y en los 15 decesos adicionales no se suministró suero antiofídico 4 . ...
Article
Full-text available
Introducción: Las mordeduras de serpiente continúan siendo un problema de salud pública, especialmente en países tropicales como Colombia. Objetivo: Caracterizar los casos de accidente ofídico atendidos en un nuevo centro de asesoría toxicológica de Medellín, Colombia. Metodología: Se realizó un estudio descriptivo, retrospectivo, revisando la base de datos donde se registra la información relacionada con la asesoría brindada por dicho centro desde el 1 de enero hasta el 31 de diciembre de 2016. Resultados: Se registraron 117 casos de accidente ofídico, de los cuales 93 (79%) eran hombres y 24 (21%) mujeres, con una mediana de edad de 32 años (rango: 2 a 82 años). El seguimiento de los casos pudo lograse en 55 de los 117 accidentes (47%), y se describieron complicaciones en 18 de los 55 (33%) pacientes. La complicación descrita con mayor frecuencia fue brote maculopapular pruriginoso asociado con la administración del suero, sin que se identificaran diferencias entre las distintas marcas de suero antiofídico utilizado. Se documentó la muerte de un paciente (0,85%). El género Bothrops produjo la mayoría de los accidentes. Discusión: Los datos obtenidos coinciden con la bibliografía publicada.
... Los accidentes ofídicos continúan siendo un problema de salud pública, especialmente en países tropicales 1,2 . La Organización Mundial de la Salud estima que anualmente 5 millones de personas sufren mordeduras por serpientes, de ellas más de 100.000 mueren y hasta 400.000 sufren amputaciones 3 . En Colombia, el Instituto Nacional de Salud (INS) reportó que durante el 2016 se presentaron 4636 casos de accidente ofídico (con una tendencia creciente en comparación con años anteriores); en los cuales se informaron 31 defunciones, 16 no fueron hospitalizadas y en los 15 decesos adicionales no se suministró suero antiofídico 4 . ...
Article
Full-text available
Introduction: Snakebites continue to be a public health problem, especially in tropical countries like Colombia. Objetive: To characterize the snakebite cases attended by a new poison center in Medellin, Colombia. Methodology: A descriptive, retrospective study was carried out, reviewing the information of the Center’s database from January1st to December 31st, 2016. Results: There were 117 cases of ophidian accidents, affecting 93 men (79%) and 24 women (21%), with a median age of 32 years (range: 2 to 82 years). The follow-up of the cases could be done in 55 of the 117 accidents (47%), and complications were described in 18 of those 55 (33%) patients. The most commonly reported complication was a pruritic maculopapular rash that was associated to serum administration, without differences between the several brands of anti-ophidian serum used. The death of one patient (0.85%) was documented. The genus Bothrops caused most of the accidents. Discussion: Our results agree with previously published data.
... While Lipps proposed that the mechanism of the peptide is to serve as a metalloproteinase inhibitor, this does not explain how the peptide could adequately neutralize the cocktail of toxins found in CA venom. This work is directed to a US snake where the market may or may not be large enough to merit a recombinant process, but the global toll of snakebite, according to the World Health Organization may be as high as five million 15 . Thus the production of a recombinant antivenom could assist developing countries where serum-based antivenoms are often difficult to acquire. ...
Article
An eleven amino acid ribosomal peptide was shown to completely neutralize Western Diamondback Rattlesnake (Crotalus atrox) venom in mice when a lethal dose of the venom was pre-incubated with the peptide prior to intravenous injection. We have expressed the peptide as a concatenated chain of peptides and cleaved them apart from an immobilized metal affinity column using a protease. After ultrafiltration steps, the mixture was shown to partially neutralize rattlesnake venom in mice. Preliminary experiments are described here that suggest a potential life-saving therapy could be developed. To date, no recombinant therapies targeting cytotoxic envenomation have been reported. This article is protected by copyright. All rights reserved.
Article
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An estimated 15% of animals are venomous, with representatives spread across the majority of animal lineages. Animals use venoms for various purposes, such as prey capture and predator deterrence. Humans have always been fascinated by venomous animals in a Janus-faced way. On the one hand, humans have a deeply rooted fear of venomous animals. This is boosted by their largely negative image in public media and the fact that snakes alone cause an annual global death toll in the hundreds of thousands, with even more people being left disabled or disfigured. Consequently, snake envenomation has recently been reclassified by the World Health Organization as a neglected tropical disease. On the other hand, there has been a growth in recent decades in the global scene of enthusiasts keeping venomous snakes, spiders, scorpions, and centipedes in captivity as pets. Recent scientific research has focussed on utilising animal venoms and toxins for the benefit of humanity in the form of molecular research tools, novel diagnostics and therapeutics, biopesticides, or anti-parasitic treatments. Continued research into developing efficient and safe antivenoms and promising discoveries of beneficial effects of animal toxins is further tipping the scales in favour of the “cure” rather than the “curse” prospect of venoms.
Article
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Snakebite envenoming causes up to 138,000 deaths and 400,000 permanently disabled victims worldwide every year. Flooding is one of the many factors that seems to influence the incidence of snakebite. The catastrophic floods from late 2018 in Kerala (India) were widely broadcast and are an example of how flooding events are related to the increased incidence of snakebite. This relationship has been mentioned regularly in scientific and grey literature, but usually quite scarcely in comparison to other topics linked to snakebite. Additionally, web media, mobile communications, and social media have started playing an important role not only in providing access to information on flooding-related snakebite events, but also in snakebite prevention at a larger scale. In order to better understand to what extent the relationship between snakebite incidence and flooding is reported and quantified and appraise the importance of mobile communications and social media in snakebite prevention and management, we performed multiple searches in generic (Google) and specialized (PubMed, Web of Science, Google Scholar) databases. We retrieved 68 scientific articles and 5 reports ranging from 1892 to 2018 mentioning or analyzing flooding and the increased incidence of snakebite. Additionally, we found 68 web media reports linking flooding and snakebite. This review indicates that the increase of snakebite incidence due to flooding has been repeatedly observed all over the world. This phenomenon could be exacerbated because of climate change, which is expected to increase the overall magnitude and frequency of flooding. However, it could also be mitigated by the role the Internet, mobile communications, and social media could play in snakebite prevention and human and animal rescue strategies during flooding.
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Envenomations are a particular type of toxic exposure resulting from human contact with biologic substances produced in specialized glands or tissues from animals, usually by cutaneous or transdermal injection. The poisoned pregnant woman poses particular challenges to the emergency room physicians, toxicology experts, and obstetrician. The emergency treatment and stabilization of the mother should take priority over the monitoring and treatment of the fetus. Up to a certain extent, although the pregnant patient goes through an acute episode of overdose or poisoning during pregnancy, the fetus might continue to be exposed to the toxic agent and environment, sometimes for several weeks. Poisoning during pregnancy represents one‐third of a percent of all toxic exposures reported in the United States. The chapter presents toxicology, short‐term problems, long‐term problems and maternal considerations for acetaminophen, amphetamines, antidepressants, carbon monoxide, cocaine, ethanol, iron and organophosphates.
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Medically relevant cases of snakebite in Europe are predominately caused by European vipers of the genus Vipera. Systemic envenoming by European vipers can cause severe pathology in humans and different clinical manifestations are associated with different members of this genus. The most representative vipers in Europe are V. aspis and V. berus and neurological symptoms have been reported in humans envenomed by the former but not by the latter species. In this study we determined the toxicological profile of V. aspis and V. berus venoms in vivo in mice and we tested the effectiveness of two antivenoms, commonly used as antidotes, in counteracting the specific activities of the two venoms. We found that V. aspis, but not V. berus, is neurotoxic and that this effect is due to the degeneration of peripheral nerve terminals at the NMJ and is not neutralized by the two tested antisera. Differently, V. berus causes a haemorrhagic effect, which is efficiently contrasted by the same antivenoms. These results indicate that the effectiveness of different antisera is strongly influenced by the variable composition of the venoms and reinforce the arguments supporting the use polyvalent antivenoms.
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The article is devoted to the crisis situation in global health connected with the problem of neglected tropical diseases and its social effects. Negative social consequences of this group of diseases, include increase in mortality and disability, are most often due to the fact that their importance for modern society is considered in the context of their epidemiological potential. As a result, diseases that are prevalent in certain regions but are not of an infectious nature can be displaced to the periphery of the health agenda. This fact leads to appropriate modifications in the behavior of international companies that form the global market for biopharmaceuticals. As the example we take the problem of snake bites, which was on June 9, 2017 included by the World Health Organization in the list of “neglected tropical diseases”. Since the beginning of the 2000s, in various tropical and subtropical countries, there have been situations called “snake bite crisis” or “serum crisis”. Increasing the cost of the main means of therapy for snake bites – specific immunoglobulins (antiserum or antivenins) leads to the fact that the health systems of developing countries are unable to purchase it, and producers lose interest in developing this kind of biopharmaceutical products. Since the early 1980s, several major producers of antivenins – Syntex, Behringwerke AG, Sanofi-Pasteur, Wyeth – have stopped production of them or have completely left the market. This resulted in a deficit of antivenins observed in several regions, which led to the destruction or distortion of the model of interaction between patients and medical structures, the revival of archaic practices that have become an alternative to modern techniques that have shown inefficiency due to the lack of a key component. It is concluded that a qualitative change in the situation is possible only as a result of the coordinated interaction of various groups of actors (representatives of the expert community, biopharmaceutical companies, national governments, health authorities and international organizations, including WHO).
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Second generation antivenomics is a translational venomics approach designed to complement in vivo preclinical neutralization assays. It provides qualitative and quantitative information on the set of homologous and heterologous venom proteins presenting antivenom-recognized epitopes and those exhibiting impaired immunoreactivity. In a situation of worrying antivenom shortage in many tropical and sub-tropical regions with high snakebite mortality and morbidity rates, such knowledge has the potential to facilitate the optimal deployment of currently existing antivenoms and to aid in the rational design of novel broad specificity antidotes. The aim of the present work was to expand the analytical capability of the immunoaffinity second-generation antivenomics platform, endowing it with the ability to determine the maximal binding capacity of an antivenom toward the different toxins present in a venom, and to quantify the fraction of venom-specific antibodies present in a given antivenom. The application of this new platform, termed third generation (3G) antivenomics, in the preclinical evaluation of antivenoms is illustrated in this paper for the case of antivenom EchiTAb-Plus-ICP® reactivity towards the toxins of homologous (B. arietans) and heterologous (N. melanoleuca) venoms.
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Snake venom toxins that activate coagulation factors are key players in the process of venom-induced coagulopathy, and account for severe clinical manifestations. The present study applies a variety of biochemical, hematological, and histopathological approaches to broadly investigate the intravascular and systemic effects of moojenactivase (MooA), the first described PIIId subclass metalloprotease isolated from Bothrops sp venom that activates coagulation factors. MooA induced consumption coagulopathy with high toxic potency, characterized by prolongation of prothrombin and activated partial thromboplastin time, consumption of fibrinogen and the plasma coagulation factors X and II, and thrombocytopenia. MooA promoted leukocytosis and expression of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, accompanied by tissue factor-dependent procoagulant activity in peripheral blood mononuclear cells. This metalloprotease also caused intravascular hemolysis, elevated plasma levels of creatine kinase-MB, aspartate transaminase, and urea/creatinine, and induced morphopathological alterations in erythrocytes, heart, kidney, and lungs associated with thrombosis and hemorrhage. Diagnosis of MooA-induced disseminated intravascular coagulation represents an important approach to better understand the pathophysiology of Bothrops envenomation and develop novel therapeutic strategies targeting hemostatic disturbances.
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Snake venoms are mixtures of numerous proteinacious components that exert diverse functional activities on a variety of physiological targets. Because the toxic constituents found in venom vary from species to species, snakebite victims can present with a variety of life-threatening pathologies related to the neurotoxic, cytotoxic and haemotoxic effects of venom. Of the 1·8 million people envenomed by snakes every year, up to 125 000 die, while hundreds of thousands survive only to suffer with life-changing long-term morbidity. Consequently, snakebite is one of the world's most severe neglected tropical diseases. Many snake venoms exhibit strong haemotoxic properties by interfering with blood pressure, clotting factors and platelets, and by directly causing haemorrhage. In this review we provide an overview of the functional activities of haemotoxic venom proteins, the pathologies they cause in snakebite victims and how their exquisite selectivity and potency make them amenable for use as therapeutic and diagnostic tools relevant for human medicine.
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The cost of producing antivenoms from recombinant human antibodies to counter the shortage of animal-derived antisera against snakebites is not as prohibitive as you imply (Nature 537, 26–28; 2016). We estimate that 500–2,000 kilograms of therapeutically active antibodies would be needed to produce enough antivenom to treat the 1 million or so people bitten annually by snakes in sub-Saharan Africa. On the basis of production data for monoclonal antibodies (N. Hammerschmidt et al. Biotechnol. J. 9, 766–775; 2014) and for oligoclonal antibody mixtures (S. K. Rasmussen et al. Arch. Biochem. Biophys. 526, 139–145; 2012), we calculate that antivenoms created from a mixture of recombinant antibodies could be produced on this scale for US5565pergram.AtypicalAfricansnakebitecouldthereforebetreatedwithapanAfricanrecombinantantibodyantivenomfor55–65 per gram. A typical African snakebite could therefore be treated with a pan-African recombinant-antibody antivenom for 30–150. This compares favourably with the wholesale cost of a typical dose of conventional antiserum ($60–600, which includes packaging and transport, as well as production, costs).
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Background Envenoming by coral snakes (Elapidae: Micrurus), although not abundant, represent a serious health threat in the Americas, especially because antivenoms are scarce. The development of adequate amounts of antielapidic serum for the treatment of accidents caused by snakes like Micrurus corallinus is a challenging task due to characteristics such as low venom yield, fossorial habit, relatively small sizes and ophiophagous diet. These features make it difficult to capture and keep these snakes in captivity for venom collection. Furthermore, there are reports of antivenom scarcity in USA, leading to an increase in morbidity and mortality, with patients needing to be intubated and ventilated while the toxin wears off. The development of an alternative method for the production of an antielapidic serum, with no need for snake collection and maintenance in captivity, would be a plausible solution for the antielapidic serum shortage. Methods and Findings In this work we describe the mapping, by the SPOT-synthesis technique, of potential B-cell epitopes from five putative toxins from M. corallinus, which were used to design two multiepitope DNA strings for the genetic immunisation of female BALB/c mice. Results demonstrate that sera obtained from animals that were genetically immunised with these multiepitope constructs, followed by booster doses of recombinant proteins lead to a 60% survival in a lethal dose neutralisation assay. Conclusion Here we describe that the genetic immunisation with a synthetic multiepitope gene followed by booster doses with recombinant protein is a promising approach to develop an alternative antielapidic serum against M. corallinus venom without the need of collection and the very challenging maintenance of these snakes in captivity.
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Background: The worldwide neglect of immunotherapeutic products for the treatment of snakebite has resulted in a critical paucity of effective, safe and affordable therapy in many Third World countries, particularly in Africa. Snakebite ranks high among the most neglected global health problems, with thousands of untreated victims dying or becoming permanently maimed in developing countries each year because of a lack of antivenom-a treatment that is widely available in most developed countries. This paper analyses the current status of antivenom production for sub-Saharan African countries and provides a snapshot of the global situation. Methods: A global survey of snake antivenom products was undertaken in 2007, involving 46 current and former antivenom manufacturers. Companies producing antivenom for use in sub-Saharan Africa were re-surveyed in 2010 and 2011. Results: The amount of antivenom manufactured for sub-Saharan Africa increased between 2007 and 2010/11, however output and procurement remained far below that required to treat the estimated 300,000-500,000 snakebite victims each year. Variable potency and inappropriate marketing of some antivenoms mean that the number of effective treatments available may be as low as 2.5% of projected needs. Five companies currently market antivenom for sale in Africa; three others have products in the final stages of development; and since 2007 one has ceased production indefinitely. Most current antivenom producers possess a willingness and capacity to raise output. However inconsistent market demand, unpredictable financial investment and inadequate quality control discourage further production and threaten the viability of the antivenom industry. Conclusion: Financial stimulus is urgently needed to identify and develop dependable sources of high-grade antivenoms, support current and emerging manufacturers, and capitalise on existing unutilised production capacity. Investing to ensure a consistent and sustainable marketplace for efficacious antivenom products will drive improvements in quality, output and availability, and save thousands of lives each year.
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India has long been thought to have more snakebites than any other country. However, inadequate hospital-based reporting has resulted in estimates of total annual snakebite mortality ranging widely from about 1,300 to 50,000. We calculated direct estimates of snakebite mortality from a national mortality survey. We conducted a nationally representative study of 123,000 deaths from 6,671 randomly selected areas in 2001-03. Full-time, non-medical field workers interviewed living respondents about all deaths. The underlying causes were independently coded by two of 130 trained physicians. Discrepancies were resolved by anonymous reconciliation or, failing that, by adjudication. A total of 562 deaths (0.47% of total deaths) were assigned to snakebites. Snakebite deaths occurred mostly in rural areas (97%), were more common in males (59%) than females (41%), and peaked at ages 15-29 years (25%) and during the monsoon months of June to September. This proportion represents about 45,900 annual snakebite deaths nationally (99% CI 40,900 to 50,900) or an annual age-standardised rate of 4.1/100,000 (99% CI 3.6-4.5), with higher rates in rural areas (5.4/100,000; 99% CI 4.8-6.0), and with the highest state rate in Andhra Pradesh (6.2). Annual snakebite deaths were greatest in the states of Uttar Pradesh (8,700), Andhra Pradesh (5,200), and Bihar (4,500). Snakebite remains an underestimated cause of accidental death in modern India. Because a large proportion of global totals of snakebites arise from India, global snakebite totals might also be underestimated. Community education, appropriate training of medical staff and better distribution of antivenom, especially to the 13 states with the highest prevalence, could reduce snakebite deaths in India.
  • B Mohapatra
Mohapatra, B. et al. PLoS Negl. Trop. Dis. 5, e1018 (2011).
  • N I Brown
Brown, N. I. PLoS Negl. Trop. Dis. 6, e1670 (2012).
  • A H Laustsen
  • B Lohse
  • B Lomonte
  • M Engmark
  • J M Gutiérrez
Laustsen, A. H., Lohse, B., Lomonte, B., Engmark, M. & Gutiérrez, J. M. Toxicon 104, 43-45 (2015).
  • H R Ramos
Ramos, H. R. et al. PLoS Negl. Trop. Dis. 10, e0004484 (2016).