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Novel Strategies for the Diagnosis and Treatment of Snakebites
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Novel Strategies for the Diagnosis and Treatment of Snakebites

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

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 120912

Special Issue Editor

Prof. Dr. Sakthivel Vaiyapuri

E-Mail Website
Guest Editor
School of Pharmacy, University of Reading, Reading RG6 6UB, UK
Interests: venom research; sequence, structure and functional analysis of venom proteins; development of diagnostic and improved therapeutic strategies for snakebites; the impact of venoms on the cardiovascular system; clinical man-agement of snakebites in patients; policy development for snakebites
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Snakebite is a major neglected tropical disease that predominantly affects rural, agricultural populations living in developing countries. Snakebites cause as many as around 100,000 deaths each year, and many more disabilities and socioeconomic ramifications. Due to the complex nature of snake venoms and, thus, their multifaceted pathological actions, the development of diagnostic and improved treatment approaches for snakebites is challenging. In recent years, several scientists have started exploring various approaches in order to develop diagnostic tests to corroborate snakebite envenomation and improved therapeutics to effectively combat snakebite-induced pathological complications. The development of monovalent antivenoms, monoclonal antibodies, toxin-specific antibodies, and small molecule inhibitors for venom proteins are some of the recent achievements in the field of venom research. Moreover, the knowledge on the understanding of the sequence, structure, and functions of a diverse range of venom components has significantly increased in the last decade. Hence, this current issue is specifically focused on publishing the recent research activities towards developing novel strategies for the diagnosis and treatment of snakebites. This issue is expected to publish original research articles, reviews, and short communications in the broad area of venom research. Since Toxins is a well-known journal in the field of venom research, we strongly believe that the articles published in this issue will reach a wide audience and aid in the development of better diagnostic and therapeutic strategies for snakebites.

Dr. Sakthivel Vaiyapuri
Guest Editor

Manuscript Submission Information

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. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a double-blind 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 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • snakebite
  • snake
  • venom
  • venom research
  • diagnostic test for snakebites
  • antivenom
  • treatment for snakebite
  • venom enzymes

Published Papers (20 papers)

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Research

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19 pages, 1935 KiB  
Article
Quality-Related Properties of Equine Immunoglobulins Purified by Different Approaches
by Sanja Mateljak Lukačević, Tihana Kurtović, Maja Lang Balija, Marija Brgles, Stephanie Steinberger, Martina Marchetti-Deschmann and Beata Halassy
Toxins 2020, 12(12), 798; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12120798 - 14 Dec 2020
Cited by 7 | Viewed by 2812
Abstract
Whole IgG antivenoms are prepared from hyperimmune animal plasma by various refinement strategies. The ones most commonly used at industrial scale are precipitation by sodium or ammonium sulphate (ASP), and caprylic acid precipitation (CAP) of non-immunoglobulin proteins. The additional procedures, which have so [...] Read more.
Whole IgG antivenoms are prepared from hyperimmune animal plasma by various refinement strategies. The ones most commonly used at industrial scale are precipitation by sodium or ammonium sulphate (ASP), and caprylic acid precipitation (CAP) of non-immunoglobulin proteins. The additional procedures, which have so far been used for experimental purposes only, are anion-exchange (AEX) and cation-exchange chromatography (CEX), as well as affinity chromatography (AC) using IgG’s Fc-binding ligands. These protocols extract the whole IgG fraction from plasma, which contains both venom-specific and therapeutically irrelevant antibodies. Such preparations represent a complex mixture of various IgG subclasses whose functional and/or structural properties, as well as relative distribution, might be affected differently, depending on employed purification procedure. The aim of this work was to compare the influence of aforementioned refinement strategies on the IgG subclass distribution, venom-specific protective efficacy, thermal stability, aggregate formation and retained impurity profile of the final products. A unique sample of Vipera ammodytes ammodytes specific hyperimmune horse plasma was used as a starting material, enabling direct comparison of five purification approaches. The highest purity was achieved by CAP and AC (above 90% in a single step), while the lowest aggregate content was present in samples from AEX processing. Albumin was the main contaminant in IgG preparations obtained by ASP and CEX, while transferrin dominantly contaminated IgG sample from AEX processing. Alpha-1B-glycoprotein was present in CAP IgG fraction, as well as in those from ASP- and AEX-based procedures. AC approach induced the highest loss of IgG(T) subclass. CEX and AEX showed the same tendency, while CAP and ASP had almost no impact on subclass distribution. The shift in IgG subclass composition influenced the specific protective efficacy of the respective final preparation as measured in vivo. AC and CEX remarkably affected drug’s venom-neutralization activity, in contrary to the CAP procedure, that preserved protective efficacy of the IgG fraction. Presented data might improve the process of designing and establishing novel downstream processing strategies and give guidance for optimization of the current ones by providing information on potency-protecting and purity-increasing properties of each purification principle. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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19 pages, 1890 KiB  
Article
In Vitro Immunological Cross-Reactivity of Thai Polyvalent and Monovalent Antivenoms with Asian Viper Venoms
by Janeyuth Chaisakul, Muhamad Rusdi Ahmad Rusmili, Jaffer Alsolaiss, Laura-Oana Albulescu, Robert A. Harrison, Iekhsan Othman and Nicholas R. Casewell
Toxins 2020, 12(12), 766; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12120766 - 03 Dec 2020
Cited by 9 | Viewed by 2357
Abstract
The intravenous administration of polyclonal antibodies known as antivenom is the only effective treatment for snakebite envenomed victims, but because of inter-specific variation in the toxic components of snake venoms, these therapies have variable efficacies against different snake species and/or different populations of [...] Read more.
The intravenous administration of polyclonal antibodies known as antivenom is the only effective treatment for snakebite envenomed victims, but because of inter-specific variation in the toxic components of snake venoms, these therapies have variable efficacies against different snake species and/or different populations of the same species. In this study, we sought to characterize the in vitro venom binding capability and in vitro cross-neutralizing activity of antivenom, specifically the Hemato Polyvalent antivenom (HPAV; The Queen Saovabha Memorial Institute (QSMI) of the Thai Red Cross Society, Thailand) and three monovalent antivenoms (QSMI) specific to Daboia siamensis, Calloselasma rhodostoma, and Trimeresurus albolabris venoms, against a variety of South Asian and Southeast Asian viper venoms (Calloselasma rhodostoma, Daboia russelii, Hypnale hypnale, Trimeresurus albolabris, Trimeresurus purpureomaculatus, Trimeresurus hageni, and Trimeresurus fucatus). Using ELISA and immunoblotting approaches, we find that the majority of protein components in the viper venoms were recognized and bound by the HPAV polyvalent antivenom, while the monospecific antivenom made against T.albolabris extensively recognized toxins present in the venom of related species, T. purpureomaculatus, T. hageni, and T. fucatus. In vitro coagulation assays using bovine plasma revealed similar findings, with HPAV antivenom significantly inhibiting the coagulopathic activities of all tested viper venoms and T. albolabris antivenom inhibiting the venoms from Malaysian arboreal pit vipers. We also show that the monovalent C. rhodostoma antivenom exhibits highly comparable levels of immunological binding and in vitro venom neutralization to venom from both Thailand and Malaysia, despite previous reports of considerable intraspecific venom variation. Our findings suggest that Thai antivenoms from QSMI may by useful therapeutics for managing snake envenomings caused by a number of Southeast Asian viper species and populations for which no specific antivenom currently exists and thus should be explored further to assess their clinical utility in treating snakebite victims. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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10 pages, 591 KiB  
Article
Exotic Snakebites Reported to Pennsylvania Poison Control Centers: Lessons Learned on the Demographics, Clinical Effects, and Treatment of These Cases
by Stephen W. Miller, Kevin C. Osterhoudt, Amanda S. Korenoski, Ketan Patel and Sakthivel Vaiyapuri
Toxins 2020, 12(12), 755; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12120755 - 29 Nov 2020
Cited by 7 | Viewed by 2801
Abstract
Exotic snakebites (i.e. from non-native species) are a rare occurrence, but they present a unique challenge to clinicians treating these patients. Poison control centers are often contacted to assist in the management and care of these medical emergencies. In this study, we analyzed [...] Read more.
Exotic snakebites (i.e. from non-native species) are a rare occurrence, but they present a unique challenge to clinicians treating these patients. Poison control centers are often contacted to assist in the management and care of these medical emergencies. In this study, we analyzed case records of the two Pennsylvania poison control centers from 2004 to 2018 to describe clinical features reported as a result of exotic snakebite envenomation. For the 15-year period reviewed, 18 exotic snakebites were reported with effects ranging from mild local tissue injury to patients who were treated with mechanical ventilation due to respiratory failure. The mean age of the patients was 35 years and males accounted for 83% of the cases. Antivenom, the only specific treatment, was administered in seven of 18 patients within an average of four h of envenomation. The procurement of antivenom against these exotic species may require substantial logistical efforts due to limited stocking of this rarely used treatment. Newer, targeted, small molecule treatments that are being currently investigated may aid in the treatment of snakebites in general. However, people should be cautious when handling these exotic species, and clinicians should be aware of these bites and relevant clinical effects in order to manage these when reported. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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15 pages, 10118 KiB  
Article
Development of a Treatment Protocol for Cobra (Naja naja) Bite Envenoming in Dogs
by Ranjith Adhikari, Lalith Suriyagoda, Amal Premarathna, Niranjala De Silva, Ashoka Dangolla, Chandima Mallawa, Indira Silva and Indika Gawarammana
Toxins 2020, 12(11), 694; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12110694 - 02 Nov 2020
Cited by 1 | Viewed by 2940
Abstract
There is limited information on clinical profiles, treatment, and management aspects of Indian cobra (Naja naja) bite envenoming in dogs in Sri Lanka. Dogs with cobra bites presented to the Veterinary Teaching Hospital (VTH), University of Peradeniya, were prospectively studied over [...] Read more.
There is limited information on clinical profiles, treatment, and management aspects of Indian cobra (Naja naja) bite envenoming in dogs in Sri Lanka. Dogs with cobra bites presented to the Veterinary Teaching Hospital (VTH), University of Peradeniya, were prospectively studied over a period of 72 months; local and systemic clinical manifestations and hematological abnormalities were recorded. We studied 116 cobra bite envenomings in dogs. A grading system was established using a combination of anatomical site of fang marks, as well as local and systemic clinical manifestations. Accordingly, treatment strategies were established using Indian polyvalent antivenom (AVS). Pain and swelling at the bite site were major clinical signs observed, while neurotoxic manifestations (mydriasis, wheezing, and crackles) were detected in most dogs. Leukocytosis was observed in 78% of them. Statistical analysis revealed that the grading scores obtained were compatible to initiate AVS administration according to the severity. The minimum number required was 2 AVS vials (range 2–12). Almost 20% of the dogs developed wheezing, crackles, hypersalivation, restlessness, and dyspnea as adverse reactions to AVS treatment. Necrotic wounds on bitten anatomical sites developed in 19% of the dogs and 2.5% developed acute kidney injuries as a consequence of envenoming crisis. Despite treatment, 3% of dogs died. No dry bites were recorded. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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13 pages, 1005 KiB  
Article
Clinical Features and Management of Snakebite Envenoming in French Guiana
by Dabor Resiere, Stéphanie Houcke, Jean Marc Pujo, Claire Mayence, Cyrille Mathien, Flaubert NkontCho, Nicaise Blaise, Magalie Pierre Demar, Didier Hommel and Hatem Kallel
Toxins 2020, 12(10), 662; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12100662 - 19 Oct 2020
Cited by 14 | Viewed by 2444
Abstract
The management of snakebite (SB) envenoming in French Guiana (FG) is based on symptomatic measures and antivenom (AV) administration (Antivipmyn Tri®; Instituto Bioclon—Mexico). Our study aimed to assess clinical manifestations, the efficacy, and safety of Antivipmyn Tri® in the management [...] Read more.
The management of snakebite (SB) envenoming in French Guiana (FG) is based on symptomatic measures and antivenom (AV) administration (Antivipmyn Tri®; Instituto Bioclon—Mexico). Our study aimed to assess clinical manifestations, the efficacy, and safety of Antivipmyn Tri® in the management of SB. Our study is a prospective observational work. It was conducted in the Intensive Care Unit (ICU) of Cayenne General Hospital between 1 January 2016 and 31 December 2019. We included all patients hospitalized for SB envenoming. Our study contained three groups (without AV, three vials, and six vials Antivipmyn Tri®). During the study period, 133 patients were included. The main clinical symptoms were edema (98.5%), pain (97.7%), systemic hemorrhage (18%), blister (14.3%), and local hemorrhage (14.3%). AV was prescribed for 83 patients (62.3%), and 17 of them (20%) developed early adverse reactions. Biological parameters at admission showed defibrinogenation in 124 cases (93.2%), International Normalized Ratio (INR) > 2 in 104 cases (78.2%), and partial thromboplastin time (PTT) > 1.5 in 74 cases (55.6%). The time from SB to AV was 9:00 (5:22–20:40). The median time from SB to achieve a normal dosage of fibrinogen was 47:00 vs. 25:30, that of Factor II was 24:55 vs. 15:10, that of Factor V was 31:42 vs. 19:42, and that of Factor VIII was 21:30 vs. 10:20 in patients without and with AV, respectively, (p < 0.001 for all factors). Patients receiving Antivipmyn Tri® showed a reduction in the time to return to normal clotting tests, as compared to those who did not. We suggest assessing other antivenoms available in the region to compare their efficacy and safety with Antivipmyn Tri® in FG. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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4 pages, 551 KiB  
Communication
Novel Snakebite Therapeutics Must Be Tested in Appropriate Rescue Models to Robustly Assess Their Preclinical Efficacy
by Cecilie Knudsen, Nicholas R. Casewell, Bruno Lomonte, José María Gutiérrez, Sakthivel Vaiyapuri and Andreas H. Laustsen
Toxins 2020, 12(9), 528; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12090528 - 19 Aug 2020
Cited by 20 | Viewed by 3974
Abstract
In the field of antivenom research, development, and manufacture, it is often advised to follow the World Health Organization’s (WHO) guidelines for the production, control, and regulation of snake antivenom immunoglobulins, which recommend the use of preincubation assays to assess the efficacy of [...] Read more.
In the field of antivenom research, development, and manufacture, it is often advised to follow the World Health Organization’s (WHO) guidelines for the production, control, and regulation of snake antivenom immunoglobulins, which recommend the use of preincubation assays to assess the efficacy of snakebite therapeutics. In these assays, venom and antivenom are mixed and incubated prior to in vivo administration to rodents, which allows for a standardizable comparison of antivenoms with similar characteristics. However, these assays are not necessarily sufficient for therapeutics with significantly different pharmacological properties than antibody-based antivenoms, such as small molecule inhibitors, nanoparticles, and other modalities. To ensure that the in vivo therapeutic utility of completely novel toxin-neutralizing molecules with no history of use in envenoming therapy and variable pharmacokinetics is properly evaluated, such molecules must also be tested in preclinical rescue assays, where rodents are first challenged with appropriate doses of venoms or toxins, followed by the administration of neutralizing modalities after an appropriate time delay to better mimic the real-life scenarios faced by human snakebite victims. Such an approach takes the venom (or toxin) toxicokinetics, the drug pharmacokinetics, and the drug pharmacodynamics into consideration. If new modalities are only assessed in preincubation assays and not subjected to evaluation in rescue assays, the publication of neutralization data may unintentionally misrepresent the actual therapeutic efficacy and suitability of the modality being tested, and thus potentially misguide strategic decision making in the research and development of novel therapies for snakebite envenoming. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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11 pages, 897 KiB  
Article
Protein Identification of Venoms of the African Spitting Cobras, Naja mossambica and Naja nigricincta nigricincta
by Ottilie Katali, Loide Shipingana, Peter Nyarangó, Mirva Pääkkönen, Erastus Haindongo, Timothy Rennie, Peter James, John Eriksson and Christian John Hunter
Toxins 2020, 12(8), 520; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080520 - 14 Aug 2020
Cited by 6 | Viewed by 4151
Abstract
Cobra snakes, including Naja mossambica and Naja nigricincta nigricincta, are one of the major groups of snakes responsible for snakebites in southern Africa, producing significant cytotoxicity and tissue damage. The venom of N. mossambica has been briefly characterised, but that of N. n. [...] Read more.
Cobra snakes, including Naja mossambica and Naja nigricincta nigricincta, are one of the major groups of snakes responsible for snakebites in southern Africa, producing significant cytotoxicity and tissue damage. The venom of N. mossambica has been briefly characterised, but that of N. n. nigricincta is not reported. The current study identifies the venom proteins of N. mossambica and N. n. nigricincta. This is achieved using sodium dodecyl sulphate (SDS)-polyacrylamide gel eletrophroresis (PAGE), followed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Most of the proteins were less than 17 kDa in both snakes. N. mossambica was found to have 75 proteins in total (from 16 protein families), whereas N.n. nigricincta had 73 (from 16 protein families). Of these identified proteins, 57 were common in both snakes. The proteins identified belonged to various families, including the three-finger toxins (3FTx), Cysteine-rich secretory proteins (CRiSP), Phospholipase A2 (PLA2) and Venom metalloproteinase M12B (SVMP). The current study contributes to the profile knowledge of snake venom compositions, which is of fundamental value in understanding the proteins that play a major role in envenomation. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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13 pages, 306 KiB  
Article
Adverse Reactions after Administration of Antivenom in Korea
by Jin Seok Shim, Hyunggoo Kang, Yongil Cho, Hyungoo Shin and Heekyung Lee
Toxins 2020, 12(8), 507; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080507 - 06 Aug 2020
Cited by 13 | Viewed by 3780
Abstract
Kovax® antivenom is the main treatment for toxins produced by the Gloydius species. However, research on adverse reactions after Kovax® antivenom administration is scarce. We aimed to identify the incidence and characteristics of adverse reactions after Kovax® antivenom administration. We [...] Read more.
Kovax® antivenom is the main treatment for toxins produced by the Gloydius species. However, research on adverse reactions after Kovax® antivenom administration is scarce. We aimed to identify the incidence and characteristics of adverse reactions after Kovax® antivenom administration. We conducted a retrospective review of the medical records of snakebite patients in Korea between January 2008 and September 2019. We identified the frequency, characteristics, and treatments of adverse reactions to Kovax® antivenom. There were 150 patients with snakebites, of whom 121 (80.7%) patients received Kovax® antivenom. Adverse reactions occurred in five patients (4.1%). Acute adverse reactions within 24 h of antivenom administration occurred in two patients (1.7%). The symptoms of patients with acute adverse reactions were nausea, diaphoresis, dizziness, and hypotension. Delayed adverse reactions that occurred 24 h after antivenom administration were reported in three patients (2.5%). One patient had a skin rash after 10 days, and two patients had fever 37 and 48 h after antivenom use. In conclusion, most patients were managed safely after Kovax® antivenom, and the incidence of adverse reactions was low. Severe adverse reactions occurred in a small percentage of patients, and there were no deaths. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
17 pages, 2683 KiB  
Article
Repurposing Cancer Drugs Batimastat and Marimastat to Inhibit the Activity of a Group I Metalloprotease from the Venom of the Western Diamondback Rattlesnake, Crotalus atrox
by Harry J. Layfield, Harry F. Williams, Divyashree Ravishankar, Amita Mehmi, Medha Sonavane, Anika Salim, Rajendran Vaiyapuri, Karthik Lakshminarayanan, Thomas M. Vallance, Andrew B. Bicknell, Steven A. Trim, Ketan Patel and Sakthivel Vaiyapuri
Toxins 2020, 12(5), 309; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12050309 - 09 May 2020
Cited by 24 | Viewed by 5827
Abstract
Snakebite envenomation causes over 140,000 deaths every year, predominantly in developing countries. As a result, it is one of the most lethal neglected tropical diseases. It is associated with incredibly complex pathophysiology due to the vast number of unique toxins/proteins present in the [...] Read more.
Snakebite envenomation causes over 140,000 deaths every year, predominantly in developing countries. As a result, it is one of the most lethal neglected tropical diseases. It is associated with incredibly complex pathophysiology due to the vast number of unique toxins/proteins present in the venoms of diverse snake species found worldwide. Here, we report the purification and functional characteristics of a Group I (PI) metalloprotease (CAMP-2) from the venom of the western diamondback rattlesnake, Crotalus atrox. Its sensitivity to matrix metalloprotease inhibitors (batimastat and marimastat) was established using specific in vitro experiments and in silico molecular docking analysis. CAMP-2 shows high sequence homology to atroxase from the venom of Crotalus atrox and exhibits collagenolytic, fibrinogenolytic and mild haemolytic activities. It exerts a mild inhibitory effect on agonist-induced platelet aggregation in the absence of plasma proteins. Its collagenolytic activity is completely inhibited by batimastat and marimastat. Zinc chloride also inhibits the collagenolytic activity of CAMP-2 by around 75% at 50 μM, while it is partially potentiated by calcium chloride. Molecular docking studies have demonstrated that batimastat and marimastat are able to bind strongly to the active site residues of CAMP-2. This study demonstrates the impact of matrix metalloprotease inhibitors in the modulation of a purified, Group I metalloprotease activities in comparison to the whole venom. By improving our understanding of snake venom metalloproteases and their sensitivity to small molecule inhibitors, we can begin to develop novel and improved treatment strategies for snakebites. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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15 pages, 2203 KiB  
Article
Potential of Matrix Metalloproteinase Inhibitors for the Treatment of Local Tissue Damage Induced by a Type P-I Snake Venom Metalloproteinase
by Lina María Preciado, Jaime Andrés Pereañez and Jeffrey Comer
Toxins 2020, 12(1), 8; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12010008 - 20 Dec 2019
Cited by 7 | Viewed by 3484
Abstract
Snake bite envenoming is a public health problem that was recently included in the list of neglected tropical diseases of the World Health Organization. In the search of new therapies for the treatment of local tissue damage induced by snake venom metalloproteinases (SVMPs), [...] Read more.
Snake bite envenoming is a public health problem that was recently included in the list of neglected tropical diseases of the World Health Organization. In the search of new therapies for the treatment of local tissue damage induced by snake venom metalloproteinases (SVMPs), we tested the inhibitory activity of peptidomimetic compounds designed as inhibitors of matrix metalloproteinases on the activities of the SVMP Batx-I, from Bothrops atrox venom. The evaluated compounds show great potential for the inhibition of Batx-I proteolytic, hemorrhagic and edema-forming activities, especially the compound CP471474, a peptidomimetic including a hydroxamate zinc binding group. Molecular dynamics simulations suggest that binding of this compound to the enzyme is mediated by the electrostatic interaction between the hydroxamate group and the zinc cofactor, as well as contacts, mainly hydrophobic, between the side chain of the compound and amino acids located in the substrate binding subsites S1 and S1 ′ . These results show that CP471474 constitutes a promising compound for the development of co-adjuvants to neutralize local tissue damage induced by snake venom metalloproteinases. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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14 pages, 2622 KiB  
Article
Immunogenic Properties of Recombinant Enzymes from Bothrops ammodytoides towards the Generation of Neutralizing Antibodies against Its Own Venom
by Herlinda Clement, Ligia Luz Corrales-García, Damaris Bolaños, Gerardo Corzo and Elba Villegas
Toxins 2019, 11(12), 702; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11120702 - 02 Dec 2019
Cited by 7 | Viewed by 2567
Abstract
Bothropic venoms contain enzymes such as metalloproteases, serine-proteases, and phospholipases, which acting by themselves, or in synergism, are the cause of the envenomation symptoms and death. Here, two mRNA transcripts, one that codes for a metalloprotease and another for a serine-protease, were isolated [...] Read more.
Bothropic venoms contain enzymes such as metalloproteases, serine-proteases, and phospholipases, which acting by themselves, or in synergism, are the cause of the envenomation symptoms and death. Here, two mRNA transcripts, one that codes for a metalloprotease and another for a serine-protease, were isolated from a Bothrops ammodytoides venom gland. The metalloprotease and serine-protease transcripts were cloned on a pCR®2.1-TOPO vector and consequently expressed in a recombinant way in E. coli (strains Origami and M15, respectively), using pQE30 vectors. The recombinant proteins were named rBamSP_1 and rBamMP_1, and they were formed by an N-terminal fusion protein of 16 amino acid residues, followed by the sequence of the mature proteins. After bacterial expression, each recombinant enzyme was recovered from inclusion bodies and treated with chaotropic agents. The experimental molecular masses for rBamSP_1 and rBamMP_1 agreed with their expected theoretical ones, and their secondary structure spectra obtained by circular dichroism were comparable to that of similar proteins. Additionally, equivalent mixtures of rBamSP_1, rBamMP_1 together with a previous reported recombinant phospholipase, rBamPLA2_1, were used to immunize rabbits to produce serum antibodies, which in turn recognized serine-proteases, metalloproteases and PLA2s from B. ammodytoides and other regional viper venoms. Finally, rabbit antibodies neutralized the 3LD50 of B. ammodytoides venom. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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Review

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8 pages, 730 KiB  
Review
The Failures of Ethnobotany and Phytomedicine in Delivering Novel Treatments for Snakebite Envenomation
by Steven A. Trim, Carol M. Trim, Harry F. Williams and Sakthivel Vaiyapuri
Toxins 2020, 12(12), 774; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12120774 - 06 Dec 2020
Cited by 5 | Viewed by 3268
Abstract
Snakebite envenomation (SBE) is a high-priority, neglected tropical disease. This devastating occupational health hazard disproportionately affects rural farming communities in tropical countries. This is exacerbated by the distribution and densities of venomous snakes, incidence of encounters, and limited access to advanced healthcare, including [...] Read more.
Snakebite envenomation (SBE) is a high-priority, neglected tropical disease. This devastating occupational health hazard disproportionately affects rural farming communities in tropical countries. This is exacerbated by the distribution and densities of venomous snakes, incidence of encounters, and limited access to advanced healthcare, including antivenom. Before the development of antivenom, desperation and spiritual beliefs led patients to experiment with a wide range of traditional treatments. Many of these treatments still survive today, particularly in regions where access to healthcare is limited. Plants are a major source of bioactive molecules, including several lifesaving medications that are widely used to this day. However, much of the research into the use of traditional plant treatments for SBE are limited to preliminary analysis or have focused on techniques used to confirm antibody efficacy that are not suitable for non-antibody-containing treatments. Modern drugs are developed through a robust pharmaceutical drug discovery and development process, which applies as much to SBE as it does to any other disease. This review discusses specifically why research into ethnobotanical practices has failed to identify or develop a novel treatment for SBE and proposes specific approaches that should be considered in this area of research in the future. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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15 pages, 3279 KiB  
Review
Providing Antivenom Treatment Access to All Brazilian Amazon Indigenous Areas: ‘Every Life has Equal Value’
by Wuelton Marcelo Monteiro, Altair Seabra de Farias, Fernando Val, Alexandre Vilhena Silva Neto, André Sachett, Marcus Lacerda, Vanderson Sampaio, Deugles Cardoso, Luiza Garnelo, João Ricardo Nickenig Vissoci, Jacqueline Sachett and Fan Hui Wen
Toxins 2020, 12(12), 772; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12120772 - 05 Dec 2020
Cited by 22 | Viewed by 3502
Abstract
Snakebites are more frequent in the Brazilian Amazon than in other parts of Brazil, representing a high cost for the health system since antivenoms are only available through medical prescription from central municipal hospitals in most cases. The need for a cold chain [...] Read more.
Snakebites are more frequent in the Brazilian Amazon than in other parts of Brazil, representing a high cost for the health system since antivenoms are only available through medical prescription from central municipal hospitals in most cases. The need for a cold chain and physicians usually restricts access to the only effective treatment of a snakebite, the antivenom. The complex topography of the rivers contributes to delays in treatment, and consequently increases the risk of severe complications, chronic sequelae and death. Thus, decentralization of antivenom treatment to primary healthcare facilities in the interior would increase access by indigenous population groups to proper healthcare. To standardize and evaluate the decentralization to low complexity indigenous healthcare units, we suggest the (i) development and validation of standardized operational procedures, (ii) training of professionals in the validated protocol in a referral health unit, (iii) implementation of the protocol in an indigenous healthcare unit, (iv) assessment of perceptions towards and acceptability of the protocol, and (v) estimation of the impact of the protocol’s implementation. We expect that antivenom decentralization would shorten the time between diagnosis and treatment and, as such, improve the prognosis of snakebites. As health cosmology among indigenous populations has an important role in maintaining their way of life, the introduction of a new therapeutic strategy to their customs must take into account the beliefs of these peoples. Thus, antivenom administration would be inserted as a crucial therapeutic tool in a world of diverse social, natural and supernatural representations. The information presented here also serves as a basis to advocate for support and promotion of health policy initiatives focused on evidence-based care in snakebite management. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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19 pages, 999 KiB  
Review
Snakebite Envenoming a Challenging Diagnosis for the Forensic Pathologist: A Systematic Review
by Alessandro Feola, Gian Luca Marella, Anna Carfora, Bruno Della Pietra, Pierluca Zangani and Carlo Pietro Campobasso
Toxins 2020, 12(11), 699; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12110699 - 03 Nov 2020
Cited by 13 | Viewed by 7766
Abstract
Snakebite envenoming (SBE) is a public health issue in developing countries. The estimated annual global incidence of snakebites is about 5.4 million snakebites per year, resulting from 1.8 to 2.7 million cases of SBE and from 81,000 to 138,000 deaths with 400,000 survivors [...] Read more.
Snakebite envenoming (SBE) is a public health issue in developing countries. The estimated annual global incidence of snakebites is about 5.4 million snakebites per year, resulting from 1.8 to 2.7 million cases of SBE and from 81,000 to 138,000 deaths with 400,000 survivors suffering permanent physical and psychological disabilities. There are more than 3000 species of snakes around the world: 600 are venomous and over 200 are considered to be medically important because of their clinical effects. The severity of SBE depends on several factors among which bite localization, snake’s size, condition of glands and teeth, bite angle and bite duration, the microflora of the snake’s mouth and victim’s skin, age of the victim, weight, health status, and victim’s activity after a bite. Snake venoms are mixtures of protein families, and each of these families contains many different toxins or toxin isoforms. Based on their effects, snake venoms can be classified as hemotoxic, neurotoxic, or cytotoxic and they can all act together involving multiple tissues and organs. When the bite is fatal, the mechanism of death is primarily related to the paralysis of respiratory muscles, which causes asphyxia and hypoxic-ischemic encephalopathy, but also anaphylactic shock, hemorrhagic shock, cardiomyopathy, acute tubular necrosis (ATN). The purpose of this literature review is to evaluate epidemiological and post-mortem examination findings in fatal SBEs in order to better understand the pathophysiological mechanisms, thus helping pathologists in defining the correct diagnosis. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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20 pages, 1253 KiB  
Review
Current Knowledge on Snake Dry Bites
by Manuela B. Pucca, Cecilie Knudsen, Isadora S. Oliveira, Charlotte Rimbault, Felipe A. Cerni, Fan Hui Wen, Jacqueline Sachett, Marco A. Sartim, Andreas H. Laustsen and Wuelton M. Monteiro
Toxins 2020, 12(11), 668; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12110668 - 22 Oct 2020
Cited by 35 | Viewed by 17711
Abstract
Snake ‘dry bites’ are characterized by the absence of venom being injected into the victim during a snakebite incident. The dry bite mechanism and diagnosis are quite complex, and the lack of envenoming symptoms in these cases may be misinterpreted as a miraculous [...] Read more.
Snake ‘dry bites’ are characterized by the absence of venom being injected into the victim during a snakebite incident. The dry bite mechanism and diagnosis are quite complex, and the lack of envenoming symptoms in these cases may be misinterpreted as a miraculous treatment or as proof that the bite from the perpetrating snake species is rather harmless. The circumstances of dry bites and their clinical diagnosis are not well-explored in the literature, which may lead to ambiguity amongst treating personnel about whether antivenom is indicated or not. Here, the epidemiology and recorded history of dry bites are reviewed, and the clinical knowledge on the dry bite phenomenon is presented and discussed. Finally, this review proposes a diagnostic and therapeutic protocol to assist medical care after snake dry bites, aiming to improve patient outcomes. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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15 pages, 1390 KiB  
Review
Venom Ophthalmia and Ocular Complications Caused by Snake Venom
by Kun-Che Chang, Yu-Kai Huang, Yen-Wen Chen, Min-Hui Chen, Anthony T. Tu and Yen-Chia Chen
Toxins 2020, 12(9), 576; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12090576 - 08 Sep 2020
Cited by 17 | Viewed by 8448
Abstract
Little is known about the detailed clinical description, pathophysiology, and efficacy of treatments for ocular envenoming (venom ophthalmia) caused by venom of the spitting elapid and other snakes, as well as ocular complications caused by snake venom injection. In this paper, we review [...] Read more.
Little is known about the detailed clinical description, pathophysiology, and efficacy of treatments for ocular envenoming (venom ophthalmia) caused by venom of the spitting elapid and other snakes, as well as ocular complications caused by snake venom injection. In this paper, we review clinical information of case reports regarding venom ophthalmia and snake venom injection with associated ocular injuries in Asia, Africa, and the United States. We also review the literature of snake venom such as their compositions, properties, and toxic effects. Based on the available clinical information and animal studies, we further discuss possible mechanisms of venom ophthalmia derived from two different routes (Duvernoy’s gland in the mouth and nuchal gland in the dorsal neck) and the pathophysiology of snake venom injection induced ocular complications, including corneal edema, corneal erosion, cataract, ocular inflammation, retinal hemorrhage, acute angle closure glaucoma, as well as ptosis, diplopia, and photophobia. Finally, we discuss the appropriate first aid and novel strategies for treating venom ophthalmia and snake envenoming. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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11 pages, 582 KiB  
Review
Novel Treatment Strategy for Patients with Venom-Induced Consumptive Coagulopathy from a Pit Viper Bite
by Eun Jung Park, Sangchun Choi, Hyuk-Hoon Kim and Yoon Seok Jung
Toxins 2020, 12(5), 295; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12050295 - 05 May 2020
Cited by 15 | Viewed by 4411
Abstract
Pit viper venom commonly causes venom-induced consumptive coagulopathy (VICC), which can be complicated by life-threatening hemorrhage. VICC has a complex pathophysiology affecting multiple steps of the coagulation pathway. Early detection of VICC is challenging because conventional blood tests such as prothrombin time (PT) [...] Read more.
Pit viper venom commonly causes venom-induced consumptive coagulopathy (VICC), which can be complicated by life-threatening hemorrhage. VICC has a complex pathophysiology affecting multiple steps of the coagulation pathway. Early detection of VICC is challenging because conventional blood tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) are unreliable for early-stage monitoring of VICC progress. As the effects on the coagulation cascade may differ, even in the same species, the traditional coagulation pathways cannot fully explain the mechanisms involved in VICC or may be too slow to have any clinical utility. Antivenom should be promptly administered to neutralize the lethal toxins, although its efficacy remains controversial. Transfusion, including fresh frozen plasma, cryoprecipitate, and specific clotting factors, has also been performed in patients with bleeding. The effectiveness of viscoelastic monitoring in the treatment of VICC remains poorly understood. The development of VICC can be clarified using thromboelastography (TEG), which shows the procoagulant and anticoagulant effects of snake venom. Therefore, we believe that TEG may be able to be used to guide hemostatic resuscitation in victims of VICC. Here, we aim to discuss the advantages of TEG by comparing it with traditional coagulation tests and propose potential treatment options for VICC. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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26 pages, 1819 KiB  
Review
Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways
by Philip E. Bickler
Toxins 2020, 12(2), 68; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12020068 - 22 Jan 2020
Cited by 49 | Viewed by 14306
Abstract
The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic effects and toxicities. Venom protein diversity and host susceptibilities determine the relative contributions of five main pathologies: neuromuscular dysfunction, [...] Read more.
The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic effects and toxicities. Venom protein diversity and host susceptibilities determine the relative contributions of five main pathologies: neuromuscular dysfunction, inflammation, coagulopathy, cell/organ injury, and disruption of homeostatic mechanisms of normal physiology. In this review, we describe how snakebite is not only a condition mediated directly by venom, but by the amplification of signals dysregulating inflammation, coagulation, neurotransmission, and cell survival. Although venom proteins are diverse, the majority of important pathologic events following envenoming follow from a small group of enzyme-like activities and the actions of small toxic peptides. This review focuses on two of the most important enzymatic activities: snake venom phospholipases (svPLA2) and snake venom metalloproteases (svMP). These two enzyme classes are adept at enabling venom to recruit homologous endogenous signaling systems with sufficient magnitude and duration to produce and amplify cell injury beyond what would be expected from the direct impact of a whole venom dose. This magnification produces many of the most acutely important consequences of envenoming as well as chronic sequelae. Snake venom PLA2s and MPs enzymes recruit prey analogs of similar activity. The transduction mechanisms that recruit endogenous responses include arachidonic acid, intracellular calcium, cytokines, bioactive peptides, and possibly dimerization of venom and prey protein homologs. Despite years of investigation, the precise mechanism of svPLA2-induced neuromuscular paralysis remains incomplete. Based on recent studies, paralysis results from a self-amplifying cycle of endogenous PLA2 activation, arachidonic acid, increases in intracellular Ca2+ and nicotinic receptor deactivation. When prolonged, synaptic suppression supports the degeneration of the synapse. Interaction between endothelium-damaging MPs, sPLA2s and hyaluronidases enhance venom spread, accentuating venom-induced neurotoxicity, inflammation, coagulopathy and tissue injury. Improving snakebite treatment requires new tools to understand direct and indirect effects of envenoming. Homologous PLA2 and MP activities in both venoms and prey/snakebite victim provide molecular targets for non-antibody, small molecule agents for dissecting mechanisms of venom toxicity. Importantly, these tools enable the separation of venom-specific and prey-specific pathological responses to venom. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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14 pages, 11981 KiB  
Review
Philodryas (Serpentes: Dipsadidae) Envenomation, a Neglected Issue in Chile
by Félix A. Urra, Alejandro Bruno Miranda-Calle and Ramiro Araya-Maturana
Toxins 2019, 11(12), 697; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11120697 - 29 Nov 2019
Cited by 6 | Viewed by 4350
Abstract
Snakebite envenomation is considered a neglected tropical disease, although it also occurs outside the tropics. In this work, we analyzed the literature on Philodryas species in Chile (Philodryas chamissonis, P. simonsii, and P. tachymenoides) from 1834 to 2019, searching [...] Read more.
Snakebite envenomation is considered a neglected tropical disease, although it also occurs outside the tropics. In this work, we analyzed the literature on Philodryas species in Chile (Philodryas chamissonis, P. simonsii, and P. tachymenoides) from 1834 to 2019, searching for epidemiological, clinical, and molecular aspects of envenomation. Ninety-one percent of the studies found regarded taxonomy, ecology, and natural history, suggesting that snakebites and venom toxins are a neglected issue in Chile. All snakebite cases reported and toxicological studies concerned the species Philodryas chamissonis. Using 185 distributional records from the literature and museum collections for this species, we show for the first time that the reported snakebite cases correlate with human population density, occurring in the Valparaiso and Metropolitan regions in Central Chile. The reduced number of snakebite cases, which were previously considered as having a low incidence in Chile, may be a consequence of under-reported cases, probably due to the inadequate publication or scarce research on this issue. Absence of information about official pharmacological treatment, post-envenoming sequels, clinical management of particular patient groups (e.g., with non-communicable diseases, pregnant women, and the elderly) was also detected. In conclusion, despite having over 185 years of literature on Chilean snakes, knowledge on the envenomation of Philodryas genus remains scarce, seriously affecting adequate medical handling during an ophidic accident. This review highlights the need to develop deep research in this area and urgent improvements to the management of this disease in Chile. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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29 pages, 3450 KiB  
Review
The Urgent Need to Develop Novel Strategies for the Diagnosis and Treatment of Snakebites
by Harry F. Williams, Harry J. Layfield, Thomas Vallance, Ketan Patel, Andrew B. Bicknell, Steven A. Trim and Sakthivel Vaiyapuri
Toxins 2019, 11(6), 363; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11060363 - 20 Jun 2019
Cited by 84 | Viewed by 18342
Abstract
Snakebite envenoming (SBE) is a priority neglected tropical disease, which kills in excess of 100,000 people per year. Additionally, many millions of survivors also suffer through disabilities and long-term health consequences. The only treatment for SBE, antivenom, has a number of major associated [...] Read more.
Snakebite envenoming (SBE) is a priority neglected tropical disease, which kills in excess of 100,000 people per year. Additionally, many millions of survivors also suffer through disabilities and long-term health consequences. The only treatment for SBE, antivenom, has a number of major associated problems, not least, adverse reactions and limited availability. This emphasises the necessity for urgent improvements to the management of this disease. Administration of antivenom is too frequently based on symptomatology, which results in wasting crucial time. The majority of SBE-affected regions rely on broad-spectrum polyvalent antivenoms that have a low content of case-specific efficacious immunoglobulins. Research into small molecular therapeutics such as varespladib/methyl-varespladib (PLA2 inhibitors) and batimastat/marimastat (metalloprotease inhibitors) suggest that such adjunctive treatments could be hugely beneficial to victims. Progress into toxin-specific monoclonal antibodies as well as alternative binding scaffolds such as aptamers hold much promise for future treatment strategies. SBE is not implicit during snakebite, due to venom metering. Thus, the delay between bite and symptom presentation is critical and when symptoms appear it may often already be too late to effectively treat SBE. The development of reliable diagnostical tools could therefore initiate a paradigm shift in the treatment of SBE. While the complete eradication of SBE is an impossibility, mitigation is in the pipeline, with new treatments and diagnostics rapidly emerging. Here we critically review the urgent necessity for the development of diagnostic tools and improved therapeutics to mitigate the deaths and disabilities caused by SBE. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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