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Open AccessArticle

Non-Native (Exotic) Snake Envenomations in the U.S., 2005–2011

by Brandon J. Warrick, Leslie V. Boyer and Steven A. Seifert

Toxins 2014, 6(10), 2899-2911; https://doi.org/10.3390/toxins6102899 - 29 Sep 2014

Cited by 27 | Viewed by 7156

Non-native (exotic) snakes are a problematic source of envenomation worldwide. This manuscript describes the current demographics, outcomes and challenges of non-native snakebites in the United States (U.S.). We performed a retrospective case series of the National Poison Data System (NPDS) database between 2005 [...] Read more.

Non-native (exotic) snakes are a problematic source of envenomation worldwide. This manuscript describes the current demographics, outcomes and challenges of non-native snakebites in the United States (U.S.). We performed a retrospective case series of the National Poison Data System (NPDS) database between 2005 and 2011. There were 258 human exposures involving at least 61 unique exotic venomous species (average = 37 per year; range = 33–40). Males comprised 79% and females 21%. The average age was 33 years with 16% less than 20 years old. 70% of bites occurred in a private residence and 86% were treated at a healthcare facility. 35% of cases received antivenom and 10% were given antibiotics. This study is compared to our previous study (1994–2004) in which there was a substantial coding error rate. Software modifications significantly reduced coding errors. Identification and acquisition of appropriate antivenoms pose a number of logistical difficulties in the management of these envenomations. In the U.S., poison centers have valuable systems and clinical roles in the provision of expert consultation and in the management of these cases. Full article

(This article belongs to the Special Issue Antivenom and Venom Therapeutics)

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540 KiB

Open AccessArticle

Okinalysin, a Novel P-I Metalloproteinase from Ovophis okinavensis: Biological Properties and Effect on Vascular Endothelial Cells

by Yumiko Komori, Eri Murakami, Kei-ichi Uchiya, Tunemasa Nonogaki and Toshiaki Nikai

Toxins 2014, 6(9), 2594-2604; https://doi.org/10.3390/toxins6092594 - 25 Aug 2014

Cited by 7 | Viewed by 5771

Abstract

A novel hemorrhagic metalloproteinase, okinalysin, was isolated from the venom of Ovophis okinavensis. It possessed caseinolytic and hemorrhagic activities, and also hydrolyzed fibrinogen and collagen. These activities were inhibited by ethylenediaminetetraacetic acid (EDTA) but not by p-amidinophenyl methanesulfonyl fluoride hydrochloride (APMSF). [...] Read more.

A novel hemorrhagic metalloproteinase, okinalysin, was isolated from the venom of Ovophis okinavensis. It possessed caseinolytic and hemorrhagic activities, and also hydrolyzed fibrinogen and collagen. These activities were inhibited by ethylenediaminetetraacetic acid (EDTA) but not by p-amidinophenyl methanesulfonyl fluoride hydrochloride (APMSF). The molecular mass of okinalysin was 22,202 Da measured by MALDI/TOF mass spectrometry. The primary structure of okinalysin was partially determined by Edman sequencing, and the putative zinc-binding domain HEXXHXXGXXH was found to be present in its structure. From these data, okinalysin is defined as a metalloproteinase belonging to a P-I class. The partial amino acid sequence of okinalysin was homologous to the C-terminus of MP 10, a putative metalloproteinase induced from transcriptome of the venom gland cDNA sequencing of O. okinavensis. Okinalysin possessed cytotoxic activity on cultured endothelial cells, and the EC₅₀ on human pulmonary artery endothelial cells was determined to be 0.6 μg/mL. The histopathological study also showed that okinalysin causes the leakage of red blood cells and neutrophil infiltration. These results indicate that destruction of blood vessels by okinalysin is one of the main causes of hemorrhage. Full article

(This article belongs to the Special Issue Antivenom and Venom Therapeutics)

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749 KiB

Open AccessArticle

The Activation Effect of Hainantoxin-I, a Peptide Toxin from the Chinese Spider, Ornithoctonus hainana, on Intermediate-Conductance Ca²⁺-Activated K⁺ Channels

by Pengfei Huang, Yiya Zhang, Xinyi Chen, Li Zhu, Dazhong Yin, Xiongzhi Zeng and Songping Liang

Toxins 2014, 6(8), 2568-2579; https://doi.org/10.3390/toxins6082568 - 21 Aug 2014

Cited by 6 | Viewed by 5323

Abstract

Intermediate-conductance Ca²⁺-activated K⁺ (IK) channels are calcium/calmodulin-regulated voltage-independent K⁺ channels. Activation of IK currents is important in vessel and respiratory tissues, rendering the channels potential drug targets. A variety of small organic molecules have been synthesized and found to [...] Read more.

Intermediate-conductance Ca²⁺-activated K⁺ (IK) channels are calcium/calmodulin-regulated voltage-independent K⁺ channels. Activation of IK currents is important in vessel and respiratory tissues, rendering the channels potential drug targets. A variety of small organic molecules have been synthesized and found to be potent activators of IK channels. However, the poor selectivity of these molecules limits their therapeutic value. Venom-derived peptides usually block their targets with high specificity. Therefore, we searched for novel peptide activators of IK channels by testing a series of toxins from spiders. Using electrophysiological experiments, we identified hainantoxin-I (HNTX-I) as an IK-channel activator. HNTX-I has little effect on voltage-gated Na⁺ and Ca²⁺ channels from rat dorsal root ganglion neurons and on the heterologous expression of voltage-gated rapidly activating delayed rectifier K⁺ channels (human ether-à-go-go-related gene; human ERG) in HEK293T cells. Only 35.2% ± 0.4% of the currents were activated in SK channels, and there was no effect on BK channels. We demonstrated that HNTX-I was not a phrenic nerve conduction blocker or acutely toxic. This is believed to be the first report of a peptide activator effect on IK channels. Our study suggests that the activity and selectivity of HNTX-I on IK channels make HNTX-I a promising template for designing new drugs for cardiovascular diseases. Full article

(This article belongs to the Special Issue Antivenom and Venom Therapeutics)

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Open AccessArticle

Immunological Cross-Reactivity and Neutralisation of European Viper Venoms with the Monospecific Vipera berus Antivenom ViperaTAb

by Nicholas R. Casewell, Ibrahim Al-Abdulla, David Smith, Ruth Coxon and John Landon

Toxins 2014, 6(8), 2471-2482; https://doi.org/10.3390/toxins6082471 - 19 Aug 2014

Cited by 33 | Viewed by 7547

Abstract

Medically important cases of snakebite in Europe are predominately caused by European vipers of the genus Vipera. The mainstay of snakebite therapy is polyclonal antibody therapy, referred to as antivenom. Here we investigate the capability of the monospecific V. berus antivenom, [...] Read more.

Medically important cases of snakebite in Europe are predominately caused by European vipers of the genus Vipera. The mainstay of snakebite therapy is polyclonal antibody therapy, referred to as antivenom. Here we investigate the capability of the monospecific V. berus antivenom, ViperaTAb^®, to cross-react with, and neutralise lethality induced by, a variety of European vipers. Using ELISA and immunoblotting, we find that ViperaTAb^® antibodies recognise and bind to the majority of toxic components found in the venoms of the Vipera species tested at comparably high levels to those observed with V. berus. Using in vivo pre-clinical efficacy studies, we demonstrate that ViperaTAb^® effectively neutralises lethality induced by V. berus, V. aspis, V. ammodytes and V. latastei venoms and at much higher levels than those outlined by regulatory pharmacopoeial guidelines. Notably, venom neutralisation was found to be superior to (V. berus, V. aspis and V. latastei), or as equally effective as (V. ammodytes), the monospecific V. ammodytes “Zagreb antivenom”, which has long been successfully used for treating European snake envenomings. This study suggests that ViperaTAb^® may be a valuable therapeutic product for treating snakebite by a variety of European vipers found throughout the continent. Full article

(This article belongs to the Special Issue Antivenom and Venom Therapeutics)

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Open AccessArticle

Ophiophagus hannah Venom: Proteome, Components Bound by Naja kaouthia Antivenin and Neutralization by N. kaouthia Neurotoxin-Specific Human ScFv

by Witchuda Danpaiboon, Onrapak Reamtong, Nitat Sookrung, Watee Seesuay, Yuwaporn Sakolvaree, Jeeraphong Thanongsaksrikul, Fonthip Dong-din-on, Potjanee Srimanote, Kanyarat Thueng-in and Wanpen Chaicumpa

Toxins 2014, 6(5), 1526-1558; https://doi.org/10.3390/toxins6051526 - 13 May 2014

Cited by 21 | Viewed by 9794

Abstract

Venomous snakebites are an important health problem in tropical and subtropical countries. King cobra (Ophiophagus hannah) is the largest venomous snake found in South and Southeast Asia. In this study, the O. hannah venom proteome and the venom components cross-reactive to [...] Read more.

Venomous snakebites are an important health problem in tropical and subtropical countries. King cobra (Ophiophagus hannah) is the largest venomous snake found in South and Southeast Asia. In this study, the O. hannah venom proteome and the venom components cross-reactive to N. kaouthia monospecific antivenin were studied. O. hannah venom consisted of 14 different protein families, including three finger toxins, phospholipases, cysteine-rich secretory proteins, cobra venom factor, muscarinic toxin, L-amino acid oxidase, hypothetical proteins, low cysteine protein, phosphodiesterase, proteases, vespryn toxin, Kunitz, growth factor activators and others (coagulation factor, endonuclease, 5’-nucleotidase). N. kaouthia antivenin recognized several functionally different O. hannah venom proteins and mediated paratherapeutic efficacy by rescuing the O. hannah envenomed mice from lethality. An engineered human ScFv specific to N. kaouthia long neurotoxin (NkLN-HuScFv) cross-neutralized the O. hannah venom and extricated the O. hannah envenomed mice from death in a dose escalation manner. Homology modeling and molecular docking revealed that NkLN-HuScFv interacted with residues in loops 2 and 3 of the neurotoxins of both snake species, which are important for neuronal acetylcholine receptor binding. The data of this study are useful for snakebite treatment when and where the polyspecific antivenin is not available. Because the supply of horse-derived antivenin is limited and the preparation may cause some adverse effects in recipients, a cocktail of recombinant human ScFvs for various toxic venom components shared by different venomous snakes, exemplified by the in vitro produced NkLN-HuScFv in this study, should contribute to a possible future route for an improved alternative to the antivenins. Full article

(This article belongs to the Special Issue Antivenom and Venom Therapeutics)

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Review

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1457 KiB

Open AccessReview

Omics Meets Biology: Application to the Design and Preclinical Assessment of Antivenoms

by Juan J. Calvete, Libia Sanz, Davinia Pla, Bruno Lomonte and José María Gutiérrez

Toxins 2014, 6(12), 3388-3405; https://doi.org/10.3390/toxins6123388 - 15 Dec 2014

Cited by 47 | Viewed by 7159

Abstract

Snakebite envenoming represents a neglected tropical disease that has a heavy public health impact worldwide, mostly affecting poor people involved in agricultural activities in Africa, Asia, Latin America and Oceania. A key issue that complicates the treatment of snakebite envenomings is the poor [...] Read more.

Snakebite envenoming represents a neglected tropical disease that has a heavy public health impact worldwide, mostly affecting poor people involved in agricultural activities in Africa, Asia, Latin America and Oceania. A key issue that complicates the treatment of snakebite envenomings is the poor availability of the only validated treatment for this disease, antivenoms. Antivenoms can be an efficacious treatment for snakebite envenoming, provided they are safe, effective, affordable, accessible and administered appropriately. The shortage of antivenoms in various regions, particularly in Sub-Saharan Africa and some parts of Asia, can be significantly alleviated by optimizing the use of current antivenoms and by the generation of novel polyspecific antivenoms having a wide spectrum of efficacy. Complementing preclinical testing of antivenom efficacy using in vivo and in vitro functional neutralization assays, developments in venomics and antivenomics are likely to revolutionize the design and preclinical assessment of antivenoms by being able to test new antivenom preparations and to predict their paraspecific neutralization to the level of species-specific toxins. Full article

(This article belongs to the Special Issue Antivenom and Venom Therapeutics)

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4302 KiB

Open AccessReview

Engineering Venom’s Toxin-Neutralizing Antibody Fragments and Its Therapeutic Potential

by Larissa M. Alvarenga, Muhammad Zahid, Anne Di Tommaso, Matthieu O. Juste, Nicolas Aubrey, Philippe Billiald and Julien Muzard

Toxins 2014, 6(8), 2541-2567; https://doi.org/10.3390/toxins6082541 - 21 Aug 2014

Cited by 45 | Viewed by 11690

Abstract

Serum therapy remains the only specific treatment against envenoming, but anti-venoms are still prepared by fragmentation of polyclonal antibodies isolated from hyper-immunized horse serum. Most of these anti-venoms are considered to be efficient, but their production is tedious, and their use may be [...] Read more.

Serum therapy remains the only specific treatment against envenoming, but anti-venoms are still prepared by fragmentation of polyclonal antibodies isolated from hyper-immunized horse serum. Most of these anti-venoms are considered to be efficient, but their production is tedious, and their use may be associated with adverse effects. Recombinant antibodies and smaller functional units are now emerging as credible alternatives and constitute a source of still unexploited biomolecules capable of neutralizing venoms. This review will be a walk through the technologies that have recently been applied leading to novel antibody formats with better properties in terms of homogeneity, specific activity and possible safety. Full article

(This article belongs to the Special Issue Antivenom and Venom Therapeutics)

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2036 KiB

Open AccessReview

Diagnosis of Snakebite and the Importance of Immunological Tests in Venom Research

by R. David G. Theakston and Gavin D. Laing

Toxins 2014, 6(5), 1667-1695; https://doi.org/10.3390/toxins6051667 - 23 May 2014

Cited by 50 | Viewed by 16072

Abstract

In many cases of envenoming following snake bite, the snake responsible for the accident remains unidentified; this frequently results in difficulty deciding which antivenom to administer to the systemically-envenomed victim, especially when only monospecific antivenoms are available. Normally the specific diagnosis of snake [...] Read more.

In many cases of envenoming following snake bite, the snake responsible for the accident remains unidentified; this frequently results in difficulty deciding which antivenom to administer to the systemically-envenomed victim, especially when only monospecific antivenoms are available. Normally the specific diagnosis of snake bite can be conveniently made using clinical and laboratory methods. Where clinical diagnosis depends upon the recognition of specific signs of envenoming in the patient, laboratory diagnosis is based on the changes which occur in envenomed victims including the detection of abnormalities in blood parameters, presence/absence of myoglobinuria, changes in certain enzyme levels, presence/absence of neurotoxic signs and the detection in the blood of specific venom antigens using immunologically-based techniques, such as enzyme immunoassay. It is the latter which is the main subject of this review, together with the application of techniques currently used to objectively assess the effectiveness of new and existing antivenoms, to assess first aid measures, to investigate the possible use of such methods in epidemiological studies, and to detect individual venom components. With this in mind, we have discussed in some detail how such techniques were developed and how they have helped in the treatment of envenoming particularly and in venom research in general. Full article

(This article belongs to the Special Issue Antivenom and Venom Therapeutics)

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