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Special Issue "Antivenom and Venom Therapeutics"

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Animal Venoms".

Deadline for manuscript submissions: closed (30 June 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Bryan Grieg Fry

Venom Evolution Laboratory, School of Biological Sciences, University of Queensland, St. Lucia, QLD, 4072, Australia
Website | E-Mail
Interests: venom molecular evolution; phylogenetics and structure-function relationships; toxins

Special Issue Information

Dear Colleagues,

Antivenom is the only scientifically-validated treatment against snakebite and is formulated as either purifyed IgGs or as pepsin (F(ab/)2)/papain (Fab) cleaved fragments raised against venoms of single (monospecific) or multiple snake species (polyspecific). Although the treatment aims to neutralize the toxic components of snake venom, its formulation frequently fails to take into account their distinct variation in representation and immunogenicity. Consequently, the often low, clinically-relevant fraction needed to achieve reversal of envenoming frequently leads to the administration of life-threatening volumes that compromise the effectiveness of the treatment and further increase its cost and availability. This Special Issue of Toxins aims to provide a comprehensive look at the challenges of antivenom therapy and the current strategies for improving such therapy.

Dr. Bryan Fry
Dr. Camila Renjifo
Guest Editors

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1400 CHF (Swiss Francs).


Keywords

  • antivenom
  • snakebites
  • immunization
  • immunoglobulins
  • snake venom
  • toxin
  • envenoming

Published Papers (8 papers)

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Research

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Open AccessArticle Non-Native (Exotic) Snake Envenomations in the U.S., 2005–2011
Toxins 2014, 6(10), 2899-2911; doi:10.3390/toxins6102899
Received: 25 August 2014 / Revised: 16 September 2014 / Accepted: 23 September 2014 / Published: 29 September 2014
Cited by 4 | PDF Full-text (574 KB) | HTML Full-text | XML Full-text
Abstract
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)
Open AccessArticle Okinalysin, a Novel P-I Metalloproteinase from Ovophis okinavensis: Biological Properties and Effect on Vascular Endothelial Cells
Toxins 2014, 6(9), 2594-2604; doi:10.3390/toxins6092594
Received: 18 July 2014 / Accepted: 18 August 2014 / Published: 25 August 2014
Cited by 1 | PDF Full-text (540 KB) | HTML Full-text | XML Full-text
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)
Open AccessArticle The Activation Effect of Hainantoxin-I, a Peptide Toxin from the Chinese Spider, Ornithoctonus hainana, on Intermediate-Conductance Ca2+-Activated K+ Channels
Toxins 2014, 6(8), 2568-2579; doi:10.3390/toxins6082568
Received: 26 May 2014 / Revised: 28 July 2014 / Accepted: 14 August 2014 / Published: 21 August 2014
PDF Full-text (749 KB) | HTML Full-text | XML Full-text
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)
Open AccessArticle Immunological Cross-Reactivity and Neutralisation of European Viper Venoms with the Monospecific Vipera berus Antivenom ViperaTAb
Toxins 2014, 6(8), 2471-2482; doi:10.3390/toxins6082471
Received: 12 June 2014 / Revised: 13 August 2014 / Accepted: 13 August 2014 / Published: 19 August 2014
Cited by 1 | PDF Full-text (818 KB) | HTML Full-text | XML Full-text
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)
Open AccessArticle Ophiophagus hannah Venom: Proteome, Components Bound by Naja kaouthia Antivenin and Neutralization by N. kaouthia Neurotoxin-Specific Human ScFv
Toxins 2014, 6(5), 1526-1558; doi:10.3390/toxins6051526
Received: 15 February 2014 / Revised: 20 April 2014 / Accepted: 5 May 2014 / Published: 13 May 2014
Cited by 3 | PDF Full-text (1418 KB) | HTML Full-text | XML Full-text
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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Open AccessReview Omics Meets Biology: Application to the Design and Preclinical Assessment of Antivenoms
Toxins 2014, 6(12), 3388-3405; doi:10.3390/toxins6123388
Received: 8 November 2014 / Revised: 3 December 2014 / Accepted: 9 December 2014 / Published: 15 December 2014
Cited by 14 | PDF Full-text (1457 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview Engineering Venom’s Toxin-Neutralizing Antibody Fragments and Its Therapeutic Potential
Toxins 2014, 6(8), 2541-2567; doi:10.3390/toxins6082541
Received: 4 June 2014 / Revised: 16 July 2014 / Accepted: 4 August 2014 / Published: 21 August 2014
Cited by 7 | PDF Full-text (4302 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview Diagnosis of Snakebite and the Importance of Immunological Tests in Venom Research
Toxins 2014, 6(5), 1667-1695; doi:10.3390/toxins6051667
Received: 13 March 2014 / Revised: 9 May 2014 / Accepted: 14 May 2014 / Published: 23 May 2014
Cited by 4 | PDF Full-text (2036 KB) | HTML Full-text | XML Full-text
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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