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Background: Progress in snakebite envenoming (SBE) therapeutics has suffered from a critical lack of data on the research and development (R&D) landscape. A database characterising this information would be a powerful tool for coordinating and accelerating SBE R&D. To address this need, we aimed to identify and categorise all active investigational candidates in development for SBE and all available or marketed products. Methodology/Principal findings: In this landscape study, publicly available data and literature were reviewed to canvas the state of the SBE therapeutics market and research pipeline by identifying, characterising, and validating all investigational drug and biologic candidates with direct action on snake venom toxins, and all products available or marketed from 2015 to 2022. We identified 127 marketed products and 196 candidates in the pipeline, describing a very homogenous market of similar but geographically bespoke products and a diverse but immature pipeline, as most investigational candidates are at an early stage of development, with only eight candidates in clinical development. Conclusions/Significance: Further investment and research is needed to address the shortfalls in products already on the market and to accelerate R&D for new therapeutics. This should be accompanied by efforts to converge on shared priorities and reshape the current SBE R&D ecosystem to ensure translation of innovation and access. Author summary: Snakebite envenoming (SBE) is a neglected tropical disease that exerts a high impact worldwide, especially in sub-Saharan Africa, Asia, and Latin America. Animal-derived antivenoms constitute the only specific, scientifically validated treatment for envenomings, although new therapeutic alternatives are being pursued. Despite the relevance of this disease, there is a critical lack of data on the research and development landscape in antivenoms and novel therapeutics. This study describes a thorough search of the state of SBE therapeutic market and research pipeline. A total of 127 marketed products and 196 candidates were identified. The current antivenom landscape is characterised by a homogeneous market of similar but geographically bespoke products needing improvement. The R&D pipeline analysis component revealed a diverse but immature picture since only eight candidates are in clinical development. This article interprets the findings of the study to provide an initial list of priority areas that sets the stage for further development of an R&D agenda to ensure translation of innovation to reduce the impact of SBE. [ABSTRACT FROM AUTHOR]

Even though there are guidelines for the management of snakebite envenoming (SBE), the use of antibiotics in this pathology remains controversial. The aim of this study is to provide a narrative review of the literature and recommendations based on the best available evidence regarding antibiotic use in SBE. We performed a narrative review of relevant literature regarding SBE and antibiotic use as prophylaxis or treatment. A total of 26 articles were included. There is wide use of antibiotics in SBE; nevertheless, infection was not necessarily documented. The antibiotics used varied according to the study, from beta lactams to lincosamide and nitroimidazoles, and from monotherapy to combined antimicrobials. The most common recommendations were to manage skin and soft tissue infections and avoid infectious complications, but these suggestions are not necessarily based on bacteriological findings. Prophylactic use of antibiotics in SBE is discouraged in most studies. Antibiotic prescription in SBE should be based on the susceptibility of microorganisms isolated from the affected tissue or identified in snakes' oral cavities. Antibiotics should be reserved only for patients with a demonstrated infection, or those at a high risk of developing an infection, i.e., presenting severe local envenoming, local signs of infection, or those with incorrect manipulation of wounds. Prospective studies are needed to correlate microbiological findings at the wound site and the response to antibiotic use. [ABSTRACT FROM AUTHOR]

SBE not only affects humans, but also domestic animals, including livestock, with negative social and economic consequences [[3]]. Unlike many infectious diseases, SBE cannot be eradicated, but its incidence and impact can be reduced through effective programs aimed at better prevention and rapid access to treatment. Snakebite envenoming (SBE) is a neglected tropical disease (NTD) of high global impact. [Extracted from the article]

Longitudinal metabolomics and lipidomics analyses were carried out on the blood plasma of mice injected intramuscularly with venoms of the viperid species Bothrops asper or Daboia russelii. Blood samples were collected 1, 3, 6, and 24 h after venom injection, and a control group of non-envenomed mice was included. Significant perturbations in metabolomics and lipidomics were observed at 1, 3, and 6 h, while values returned close to those of control mice by 24 h, hence reflecting a transient pattern of metabolic disturbance. Both venoms induced significant changes in amino acids, as well as in several purines and pyrimidines, and in some metabolites of the tricarboxylic acid cycle. KEGG analysis of metabolic pathways that showed those with the greatest change included aminoacyl tRNA synthesis and amino acid biosynthesis and metabolism pathways. With regard to lipid metabolism, there was an increase in triglycerides and some acyl carnitines and a concomitant drop in the levels of some phospholipids. In addition, envenomed mice had higher levels of cortisol, heme, and some oxidative stress markers. The overall pattern of metabolic changes in envenomed mice bears similarities with the patterns described in several traumatic injuries, thus underscoring a metabolic response/adaptation to the injurious action of the venoms. [ABSTRACT FROM AUTHOR]

The phagocytic activity of macrophages activated with MT-II, a Lys-49 PLA 2 homolog, and MT-III, an Asp-49 PLA 2 , from Bothrops asper snake venom, was investigated in this study using a pharmacological approach. Stimulating thioglycollate-elicited macrophages with both venom components enhanced their ability to phagocytose non-opsonized zymosan particles. MT-II and MT–III–induced phagocytosis was drastically inhibited by pretreating cells with L-NAME, aminoguanidine or L-NIL, cNOS or iNOS inhibitors, or with ODQ (sGC inhibitor) or Rp-cGMPS (PKG inhibitor). These results indicate that the NO/sGC/GMP/PKG pathway plays an essential role in the β-glucan-mediated phagocytosis induced in macrophages by these venom-secretory PLA 2 s. [Display omitted] • -The PLA2s MT-II and MT-III induced zymosan phagocytosis. • -Nitric oxide is involved in both PLA 2 s-induced phagocytosis. • -sGC, GMP, and PKG are signaling pathways that play a role in phagocytosis induced by PLA 2 s. [ABSTRACT FROM AUTHOR]

Instituto Butantan (São Paulo, Brazil) and Instituto Clodomiro Picado (San José, Costa Rica) are public institutions devoted to scientific and technological research, production of antivenoms and other immunobiologicals, and a variety of public health interventions aimed at confronting the problem of snakebite envenoming in their countries and elsewhere. In the context of the 120th anniversary of Instituto Butantan, this work describes the historical developments in the relationship between these institutions, which has evolved into a solid cooperation platform in science, technology, and public health. The relationship between Instituto Butantan and Costa Rica started early in the 20th century, with the provision of Brazilian antivenoms to Costa Rica through the coordination of Instituto Butantan and the health system of Costa Rica, with the leadership of Clodomiro Picado Twight. After the decade of 1980, a prolific collaborative network has been established between Instituto Butantan and Instituto Clodomiro Picado (founded in 1970) in the areas of scientific and technological research in pharmacology, biochemistry, experimental pathology, immunology, and public health, as well as in antivenom development, production, preclinical evaluation, and quality control. In addition, both institutions have played a key role in the integration of regional efforts in Latin America to create a network of public institutions devoted to antivenom production and quality control, in close coordination with the Pan American Health Organization (PAHO). This long-standing partnership is an example of a highly productive south-south cooperation under a frame of solidarity and public well-being. [Display omitted] • Instituto Butantan and Instituto Clodomiro Picado have had a long collaboration. • Instituto Butantan provided antivenoms to Costa Rica in the 20th century. • A collaborative research agenda had developed between these institutions. • Both institutions have played a key role in regional public health efforts. • This collaboration has been based on a frame of solidarity and mutual benefit. [ABSTRACT FROM AUTHOR]

The phospholipase A 2 (PLA 2) inhibitors varespladib (LY315920) and its orally available derivative methyl-varespladib (LY333013) have been proposed as potential therapies for the treatment of snakebite envenomings in which toxicity depends on the action of PLA 2 s. In this study, the ability of LY315920 to abrogate the effect of the potent neurotoxic venom of Oxyuranus scutellatus (taipan) was assessed using the mouse phrenic nerve-diaphragm preparation. LY315920 inhibited the venom when (a) incubated with venom before addition to the medium; (b) added to the medium before addition of venom, and; (c) added to the medium within 30 min after addition of venom, and even after the onset of decline in twitch response. This contrasts with previous results with antivenom using the same experimental model, in which the window of time when antibodies are effective is shorter than 10 min. It is proposed that such differences may depend either on the higher affinity of the inhibitor for PLA 2 s or on the possibility that LY315920 reaches the cytosol of the nerve terminals, inhibiting neurotoxins that have been internalized. Our findings bear implications on the therapeutic potential of varespladib in neurotoxic snakebite envenomings mediated by presynaptically-acting PLA 2 s. • Oxyuranus scutellatus venom inhibits neuromuscular transmission ex vivo. • Varespladib inhibits the neuromuscular blocking effect of Oxyuranus scutellatus venom. • Varespladib halts the neuromuscular blockade when added after venom. • Varespladib is effective at halting the blockage at times when antivenom is ineffective. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases have been implicated in diabetic microvascular complications. However, little is known about the pathophysiological links between MMP-10 and the renin-angiotensin system (RAS) in diabetic kidney disease (DKD). We tested the hypothesis that MMP-10 may be up-regulated in early stage DKD, and could be down-regulated by angiotensin II receptor blockade (telmisartan). Serum MMP-10 and TIMP-1 levels were measured in 268 type 2 diabetic subjects and 111 controls. Furthermore, histological and molecular analyses were performed to evaluate the renal expression of Mmp10 and Timp1 in a murine model of early type 2 DKD (db/db) after telmisartan treatment. MMP-10 (473 ± 274 pg/ml vs. 332 ± 151; p = 0.02) and TIMP-1 (573 ± 296 ng/ml vs. 375 ± 317; p < 0.001) levels were significantly increased in diabetic patients as compared to controls. An early increase in MMP-10 and TIMP-1 was observed and a further progressive elevation was found as DKD progressed to end-stage renal disease. Diabetic mice had 4-fold greater glomerular Mmp10 expression and significant albuminuria compared to wild-type, which was prevented by telmisartan. MMP-10 and TIMP-1 are increased from the early stages of type 2 diabetes. Prevention of MMP-10 upregulation observed in diabetic mice could be another protective mechanism of RAS blockade in DKD. [ABSTRACT FROM AUTHOR]

Travel writing had a significant impact on the way cannibalism was to be interpreted and diffused from the sixteenth century onwards. By analyzing how much our current understanding of anthropophagy owes to the discourse of travel writing and the simultaneous interaction between concept and medium, a better understanding of its implications in philosophical, political and scientific discourse can be perceived. It also elaborates on how we built self-identification through the uses of fears and cultural stereotypes. A quick glance at the structure of travel writing helps conceptualize how the encounter with Native Americans by Christopher Columbus transformed the Western perceptions of cannibalism and determined relations with other peoples in the following centuries, from Polynesians to Africans. The repercussions of this dialectical process are still palpable today. [ABSTRACT FROM AUTHOR]

South American rattlesnakes (Crotalus durissus spp) and coral snakes (Micrurus sp) venoms are characterized by inducing a limited inflammatory innate immune response, in contrast to Bothrops sp snake venoms which exert a prominent inflammatory activity. Some Crotalus durissus spp venoms, in addition, exert immunosuppressive activities that hamper the development of neutralizing antibodies in animals immunized for antivenom production. Micrurus sp venoms are rich in low molecular mass neurotoxins that elicit a limited immune response. These characteristics make it difficult to generate antivenoms of high neutralizing activity. Therefore, the study of the mechanisms operating behind this limited immune response to venoms is relevant from both fundamental and practical perspectives. This review summarizes key aspects of the immune response to these venoms and discusses some pending challenges to further understand these phenomena and to improve antivenom production. [Display omitted] • South American coral and rattlesnake venoms induce limited inflammation. • Crotalus durissus spp venoms exert immunosuppressive activities attributed to crotoxin. • Micrurus sp toxins such as 3-FTXs, are poorly immunogenic. • This type of venom elicits a poor immune response in immunized animals. [ABSTRACT FROM AUTHOR]

Snakebite envenoming (SBE) is a neglected tropical disease that kills and maims hundreds of thousands of people yearly, particularly in impoverished rural settings of the Global South. Understanding the complexity of SBE and tackling this disease demands a transdisciplinary, One Health approach. There is a long-standing research tradition on SBE in toxinology and human medicine. In contrast, other disciplines, such as veterinary medicine or social sciences, still need to be better developed in this field, especially in countries with a high incidence of SBE. Broadening the disciplinary landscape, connecting various research approaches, methods, and data across disciplines and sectors, and engaging with communities affected by SBE in implementing evidence-based solutions are needed. This review summarizes areas that require strengthening to better understand the complexity of SBE and to generate a robust body of knowledge to be translated into effective public health interventions. [Display omitted] • Snakebite envenoming has been traditionally studied within the field of Toxinology. • To grasp the complexity of snakebite envenoming it is necessary to broaden the disciplinary landscape. • Social sciences provide relevant tools to expand our understanding of the multiple factors associated with snakebites. • The search for transdisciplinarity will provide novel tools to understand and confront snakebite envenoming. [ABSTRACT FROM AUTHOR]

Seven laboratories manufactured antivenoms, whereas 5 laboratories did not. A network of public laboratories devoted to the production and quality control of antivenoms was established in this region in the last decade [[4]], which has recently led to the creation of the Latin American Network of Public Antivenom Manufacturing Laboratories (RELAPA, I Red Latinoamericana de Laboratorios Públicos Productores de Antivenenos i ) [[6]]. The survey included the following aspects: (a) What was the demand and the production of antivenoms (including snake, scorpion, spider, and caterpillar antivenoms) during the period January 2020 to July 2020?. [Extracted from the article]

Abstract Dealing with the 41K interference during 41Ca measurement with low energy AMS systems is challenging. The detection of 39K to correct the measured 41Ca/40Ca ratios is a powerful tool that improves precision and accuracy. However, the study of the sources of this interference can help to reduce it to its minimum. In this work, it is shown that iron is a factor enhancing the production of the 41K interference, since the (41K57Fe)− ion has the same mass as (41K19F 3)−. To validate this observation, we measured 57Fe2+ together with 41M2+ (all ions with mass 41) and 39K2+ in a blank sample and an aluminum target at the 600 kV AMS system at ETH Zurich. We also show the temporal evolution of 41M/40Ca and 39K/40Ca ratios in two blank samples during a measurement on the 1 MV AMS system at CNA Seville. Even when unstable behavior for these ratios is observed for one of the blanks, the relationship between both, 41M/39K, is relatively stable over time. This supports the accuracy of the K–correction method, providing that it is applied sequence by sequence. Two programs, one for each of these compact AMS systems, were written in FORTRAN code to deal with the complexity of the data analysis due to the K-correction. [ABSTRACT FROM AUTHOR]

This study describes the basic epidemiological features of snakebites in El Salvador for the period 2014–2019 on the basis of data provided by the national system of information on morbidity and mortality (Sistema de Morbi-Mortalidad via Web , SIMMOW) of the Ministry of Health of El Salvador. The total number of cases per year ranged from 161 (2017) to 215 (2016). Incidences ranged from 2.52 cases to 3.38 cases per 100,000 population per year, corresponding to the years 2017 and 2016, respectively. Five deaths were recorded in the six-year period, four in 2015 and one in 2016, for a case fatality rate of 0.44%. Snakebites peaked during the rainy season (May to November) and mostly affected people in the age groups of 10–30 years. The male/female ratio was 1.59. The Departments (local political units) showing the highest number of cases were Santa Ana, Libertad, Chalatenango, Sonsonate, and La Unión. Most cases were attended at departmental and regional hospitals (second level of attention). The incidence and mortality due to snakebite envenoming in El Salvador are the lowest reported for Central America. This may be related to the fact that Bothrops asper , the medically most important snake species in the region, is not distributed in El Salvador, where the rattlesnake Crotalus simus predominates. Image 1 • The main epidemiological features of snakebites in El Salvador for the period 2014–2019 are described. • A total of 1130 cases were registered for this period, for an annual mean of 188 cases. • Incidence ranged from 2.52 to 3.38 cases per 100,000 population per year, for the years 2017 and 2016, respectively. • Five deaths were recorded for this six-year interval. • El Salvador has the lowest incidence of snakebites in the whole Central American region. [ABSTRACT FROM AUTHOR]

Introduction: The transition to college life can impact the mental health of students. There are mental health care strategies that promote connection with the body's internal signals, which can help to improve mental well-being, manage emotions, and reduce the risk of suicide in university students. Aim: This study aimed to examine the association between interoceptive body awareness variables and suicidal orientation in a sample of 169 undergraduate students in Colombia. Methods: An observational, cross-sectional study was conducted in 2023 with Colombian students as the participants. Results: The findings revealed a significant and moderately negative correlation between the Multidimensional Assessment of Interoceptive Awareness (MAIA) total score and the Inventory of Suicide Orientation (ISO-30) total score (r = −0.54, p < 0.001). Confidence and self-regulation were identified as the most influential factors in the relationship between MAIA and ISO-30. Significant correlations were observed (p < 0.001), indicating moderate correlation values ranging from −0.43 to −0.57. Discussion: Our findings support the existence of a negative correlation between interoceptive body awareness and suicidal orientation. Further research is needed to better understand this relationship and to develop specific interventions based on body awareness to prevent suicide orientation. Conclusion: There are practical implications associated with recognizing the importance of body awareness in relation to decreasing suicidal orientation, and multidisciplinary teams addressing mental health can incorporate this knowledge. [ABSTRACT FROM AUTHOR]

Phagocytosis, a process involved in host defense, requires coordination of a variety of signaling reactions. MT-II, a catalytically-inactive Lys49-PLA 2 ¸ and MT-III, an active Asp49-PLA 2 isolated from Bothrops asper snake venom, activate phagocytosis in macrophages. In this study the signal pathways mediating zymosan phagocytosis, focusing in lipidic second messengers, were investigated. Macrophages collected from male Swiss mouse peritoneum were obtained 96 h after i.p. injection of thioglycollate. Phagocytosis was evaluated with non-opsonized zymosan in the presence or absence of specific inhibitors. Data showed that both venom PLA 2 s increased phagocytosis. Zileuton, Etoricoxib, PACOCF 3 (5-LO, COX-2 and iPLA 2 inhibitors, respectively), as well as WEB2170 (PAF receptor antagonist) significantly reduced phagocytosis induced by both venom PLA 2 s. However, Indomethacin (COX-1/COX-2 inhibitor) and Montelukast (CysL receptor antagonist) did not affect the toxins-induced phagocytosis. Moreover, while PACOCF3 (iPLA 2 inhibitor), reduced the phagocytosis induced by MT-II and MT-III, AACOCF 3 (cPLA 2 inhibitor) significantly reduced the MT-II, but not MT-III-induced phagocytosis. These data suggest the effect of both sPLA 2 s depends on iPLA 2 and that the effect of MT-II depends on activation of cPLA 2 . COX-2 and 5-LO-derived metabolites as well as PAF are involved in the signaling events required for phagocytosis induced by both venom sPLA 2 s. [ABSTRACT FROM AUTHOR]

Snakebite envenoming by viperid species, and by some elapids, is characterized by a complex pattern of tissue damage at the anatomical site of venom injection. In severe cases, tissue destruction may be so extensive as to lead to permanent sequelae, with serious pathophysiological, social and psychological consequences. Significant advances have been performed in the study of venom-induced tissue damage, including identification and characterization of the toxins involved, insights into the mechanisms of action of venoms and toxins, and study of tissue responses to venom-induced injury. Nevertheless, much remains to be known and understood on the pathogenesis of these alterations. This review focuses on some of the pending issues in the topic of snake venom-induced local tissue damage. The traditional ‘reductionist’ approach, which has predominated in the study of snake venoms and their actions, needs to be complemented by more integrative and holistic perspectives aimed at capturing the complexity of these pathological alterations. Future advances in the study of these topics will certainly pave the way for innovative therapeutic interventions, with the goal of reducing the impact of this aspect of snakebite envenoming. [ABSTRACT FROM AUTHOR]

The preclinical evaluation of the neutralizing efficacy of antivenoms is mandatory before a product is introduced for clinical use. The World Health Organization (WHO) guidelines for antivenoms categorize the tests used in preclinical studies as ‘essential assay’ (neutralization of lethality) and ‘additional recommended assays’ (neutralization of other relevant toxic activities). The present review presents an overview of the methodological aspects of snake antivenom preclinical efficacy tests, and summarizes the studies performed in this subject on antivenoms used in Latin America and the Caribbean. General trends emerging from this analysis show that: (a) Bothrops antivenoms have a broad spectrum of neutralizing efficacy against venoms of snakes of the genera Agkistrodon , Atropoides , Bothriechis , Bothrops , Cerrophidion , and Porthidium . (b) Crotalus antivenoms show a dichotomic pattern of efficacy depending on whether the venoms used for immunization are crotoxin-rich or metalloproteinase-rich. (c) A complete neutralization of Lachesis sp venoms is achieved only by antivenoms that include Lachesis sp venoms in the immunizing mixture. (d) Micrurus sp venoms have a high immunological heterogeneity which impacts in the cross-neutralization by available antivenoms. There is a need to further expand the knowledge base of the preclinical efficacy of antivenoms in Latin America and the Caribbean. [ABSTRACT FROM AUTHOR]

Most of the anthropogenic radionuclide 129 I released to the marine environment from the nuclear fuel reprocessing plants (NFRP) at Sellafield (England) and La Hague (France) is transported to the Arctic Ocean via the North Atlantic Current and the Norwegian Coastal Current. 129 I concentrations in seawater provides a powerful and well-established radiotracer technique to provide information about the mechanisms which govern water mass transport in the Nordic Seas and the Arctic Ocean and is gaining importance when coupled with other tracers (e.g. CFC, 236 U). In this work, 129 I concentrations in surface and depth profiles from the Nordic Seas and the North Atlantic (NA) Ocean collected from four different cruises between 2011 and 2012 are presented. This work allowed us to i) update information on 129 I concentrations in these areas, required for the accurate use of 129 I as a tracer of water masses; and ii) investigate the formation of deep water currents in the eastern part of the Nordic Seas, by the analysis of 129 I concentrations and temperature-salinity (T-S) diagrams from locations within the Greenland Sea Gyre. In the Nordic Seas, 129 I concentrations in seawater are of the order of 10 9 at·kg − 1 , one or two orders of magnitude higher than those measured at the NA Ocean, not so importantly affected by the releases from the NFRP. 129 I concentrations of the order of 10 8 atoms·kg − 1 at the Ellet Line and the PAP suggest a direct contribution from the NFRP in the NA Ocean. An increase in the concentrations in the Nordic Seas between 2002 and 2012 has been detected, which agrees with the temporal evolution of the 129 I liquid discharges from the NFRPs in years prior to this. Finally, 129 I profile concentrations, 129 I inventories and T-S diagrams suggest that deep water formation occurred in the easternmost area of the Nordic Seas during 2012. [ABSTRACT FROM AUTHOR]

We present a detailed study of the performance parameters for 41 Ca measurements at the 1 MV AMS system at the Centro Nacional de Aceleradores (CNA) in Seville. Mixing CaF 2 with Ag, we get stable ( 40 CaF 3 ) − currents between 50 and 100 nA. Transmission of the 2+ state in the He stripper is 41%, while optical transmission in the HE sector is typically higher than 95%. At low energies we cannot separate 41 Ca from the isobar 41 K at the detector, but the interference is reduced by using ( 41 CaF 3 ) − ions. The remaining contribution is corrected by measurement of the other stable isotope of potassium, 39 K, to estimate this interference (K-correction). After this correction, we reach a 41 Ca/ 40 Ca background level between 5 × 10 −12 and 8 × 10 −12 , making possible measurements of 41 Ca/ 40 Ca ratios higher than 4 × 10 −11 . Intercomparisons with the 0.6 MV AMS system at ETH Zurich show a quite good correlation. [ABSTRACT FROM AUTHOR]

Animal-derived antivenoms constitute the mainstay in the therapy of snakebite envenoming. The efficacy of antivenoms to neutralize toxicity of medically-relevant snake venoms has to be demonstrated through meticulous preclinical testing before their introduction into the clinical setting. The gold standard in the preclinical assessment and quality control of antivenoms is the neutralization of venom-induced lethality. In addition, depending on the pathophysiological profile of snake venoms, the neutralization of other toxic activities has to be evaluated, such as hemorrhagic, myotoxic, edema-forming, dermonecrotic, in vitro coagulant, and defibrinogenating effects. There is a need to develop laboratory assays to evaluate neutralization of other relevant venom activities. The concept of the 3Rs (Replacement, Reduction, and Refinement) in Toxinology is of utmost importance, and some advances have been performed in their implementation. A significant leap forward in the study of the immunological reactivity of antivenoms against venoms has been the development of "antivenomics", which brings the analytical power of mass spectrometry to the evaluation of antivenoms. International partnerships are required to assess the preclinical efficacy of antivenoms against snake venoms in different regions of the world in order to have a detailed knowledge on the neutralizing profile of these immunotherapeutics. [ABSTRACT FROM AUTHOR]

Jay W. Fox and José María Gutiérrez recently finished editing a Special Issue on the topic "Snake Venom Metalloproteinases" in Toxins. The Special Issue covers a wide range of topics, including the molecular evolution and structure of snake venom metalloproteinases (SVMPs), the mechanisms involved in the generation of diversity of SVMPs, the mechanism of action of SVMPs, and their role in the pathophysiology of envenomings, with implications for improving the therapy of envenomings. In this interview, we discussed with JayW. Fox and José María Gutiérrez their research on the SVMPs and their perspectives on the future trends and challenges for studying snake venoms. [ABSTRACT FROM AUTHOR]

The deliberations and conclusions of a Hinxton Retreat convened in September 2015, entitled "Mechanisms to reverse the public health neglect of snakebite victims" are reported. The participants recommended that the following priority actions be included in strategies to reduce the global impact of snake envenoming: (a) collection of accurate global snakebite incidence, mortality and morbidity data to underpin advocacy efforts and help design public health campaigns; (b) promotion of (i) public education prevention campaigns; (ii) transport systems to improve access to hospitals and (iii) establishment of regional antivenom-efficacy testing facilities to ensure antivenoms' effectiveness and safety; (c) exploration of funding models for investment in the production of antivenoms to address deficiencies in some regions; (d) establishment of (i) programs for training in effective first aid, hospital management and post-treatment care of victims; (ii) a clinical network to generate treatment guidelines and (iii) a clinical trials system to improve the clinical management of snakebite; (e) development of (i) novel treatments of the systemic and local tissue-destructive effects of envenoming and (ii) affordable, simple, point-of-care snakebite diagnostic kits to improve the accuracy and rapidity of treatment; (f) devising and implementation of interventions to help the people and communities affected by physical and psychological sequelae of snakebite. [ABSTRACT FROM AUTHOR]

Snake venom metalloproteinases (SVMPs) affect the extracellular matrix (ECM) in multiple and complex ways. Previously, the combination of various methodological platforms, including electron microscopy, histochemistry, immunohistochemistry, and Western blot, has allowed a partial understanding of such complex pathology. In recent years, the proteomics analysis of exudates collected in the vicinity of tissues affected by SVMPs has provided novel and exciting information on SVMP-induced ECM alterations. The presence of fragments of an array of ECM proteins, including those of the basement membrane, has revealed a complex pathological scenario caused by the direct action of SVMPs. In addition, the time-course analysis of these changes has underscored that degradation of some fibrillar collagens is likely to depend on the action of endogenous proteinases, such as matrix metalloproteinases (MMPs), synthesized as a consequence of the inflammatory process. The action of SVMPs on the ECM also results in the release of ECM-derived biologically-active peptides that exert diverse actions in the tissue, some of which might be associated with reparative events or with further tissue damage. The study of the effects of SVMP on the ECM is an open field of research which may bring a renewed understanding of snake venom-induced pathology. [ABSTRACT FROM AUTHOR]

Snake venoms are composed mainly of a mixture of proteins and peptides. Notably, all snake venom toxins have been assigned to a small number of protein families. Proteomic studies on snake venoms have recently identified the presence of Kazal-type inhibitor-like proteins in the neotropical arboreal snakes Bothriechis schlegelii and Bothriechis supraciliaris . In the present study, a Kazal-type component from B. schlegelii , named Kazal-type inhibitor-like protein (KTIL), has been completely sequenced and characterized for the first time. This protein, which contains 54 amino acid residues, shows sequence similarity to the third domain of the ovomucoid from avian species, which is a Kazal-like domain. KTIL did not inhibit the enzymatic activity of various serine proteinases at pH = 7.2 or pH = 8.0, but partially inhibited the activity of trypsin at pH = 5.4, and the only toxic effect in mice observed after different in vivo tests was the induction of footpad edema. KTIL was not lethal when injected in mice or chickens. The presence of Kazal-type proteins and mRNA only in species of the genus Bothriechis suggests a genus recruitment event in the early-Middle Miocene, the estimated time of emergence of this clade. [ABSTRACT FROM AUTHOR]

The historical development of discoveries and conceptual frames for understanding the hemorrhagic activity induced by viperid snake venoms and by hemorrhagic metalloproteinases (SVMPs) present in these venoms is reviewed. Histological and ultrastructural tools allowed the identification of the capillary network as the main site of action of SVMPs. After years of debate, biochemical developments demonstrated that all hemorrhagic toxins in viperid venoms are zinc-dependent metalloproteinases. Hemorrhagic SVMPs act by initially hydrolyzing key substrates at the basement membrane (BM) of capillaries. This degradation results in the weakening of the mechanical stability of the capillary wall, which becomes distended owing of the action of the hemodynamic biophysical forces operating in the circulation. As a consequence, the capillary wall is disrupted and extravasation occurs. SVMPs do not induce rapid toxicity to endothelial cells, and the pathological effects described in these cells in vivo result from the mechanical action of these hemodynamic forces. Experimental evidence suggests that degradation of type IV collagen, and perhaps also perlecan, is the key event in the onset of microvessel damage. It is necessary to study this phenomenon from a holistic, systemic perspective in which the action of other venom components is also taken into consideration. [ABSTRACT FROM AUTHOR]

During 45 years, the Instituto Clodomiro Picado (ICP, University of Costa Rica) has developed an ambitious scientific, technological, productive, and social program aimed at providing a better understanding of snakes and their venoms, contributing to the development, production and distribution of antivenoms, improving the prevention and management of snakebite envenomings, and strengthening human resources in science and technology. Among other topics, its research agenda has focused on the local tissue alterations induced by viperid snake venoms, i.e. myonecrosis, hemorrhage, dermonecrosis, extracellular matrix degradation, lymphatic vessel damage, and inflammation. In addition, the preclinical efficacy of antivenoms has been thoroughly investigated, together with the technological development of novel antivenoms. ICP's project has been based on a philosophical frame characterized by: (a) An integrated approach for confronting the problem of snakebites, involving research, production, extension activities, and teaching; (b) a cooperative and team work perspective in the pursuit of scientific, technological, productive, and social goals; (c) a search for excellence and continuous improvement in the quality of its activities; and (d) a vision of solidarity and compassion, based on the realization that snakebite envenomings mostly affect impoverished vulnerable populations in the rural settings of developing countries. A key aspect in this program has been the consolidation of international partnerships with groups of all continents, within a frame of academic and social cooperation, some of which are described in this review. [ABSTRACT FROM AUTHOR]

Four specimens of the olive sea snake, Aipysurus laevis , were collected off the coast of Western Australia, and the venom proteome was characterized and quantitatively estimated by RP-HPLC, SDS-PAGE, and MALDI-TOF-TOF analyses. A. laevis venom is remarkably simple and consists of phospholipases A 2 (71.2%), three-finger toxins (3FTx; 25.3%), cysteine-rich secretory proteins (CRISP; 2.5%), and traces of a complement control module protein (CCM; 0.2%). Using a Toxicity Score, the most lethal components were determined to be short neurotoxins. Whole venom had an intravenous LD 50 of 0.07 mg/kg in mice and showed a high phospholipase A 2 activity, but no proteinase activity in vitro . Preclinical assessment of neutralization and ELISA immunoprofiling showed that BioCSL Sea Snake Antivenom was effective in cross-neutralizing A. laevis venom with an ED 50 of 821 μg venom per mL antivenom, with a binding preference towards short neurotoxins, due to the high degree of conservation between short neurotoxins from A. laevis and Enhydrina schistosa venom. Our results point towards the possibility of developing recombinant antibodies or synthetic inhibitors against A. laevis venom due to its simplicity. [ABSTRACT FROM AUTHOR]

The article offers the authors' insights regarding the need for social research integration to multidisciplinary approach in the study of snakebite envenoming as a global health problem. Topics discussed include the use of community surveys of mortality and snakebite incidence as reliable data, the identification of the barriers to avail and access antivenoms and how to improve the trainings of health personnels to address the local needs of snakebite treatment.

However, envenoming by animal bites and stings goes beyond snakebite and includes scorpions and spiders, insects, jellyfish, and other marine creatures. Envenomings from animal bites and stings are particularly frequent in developing countries where they dramatically affect the most deprived populations. [Extracted from the article]

The venom proteome of the monocled cobra, Naja kaouthia , from Thailand, was characterized by RP-HPLC, SDS-PAGE, and MALDI-TOF-TOF analyses, yielding 38 different proteins that were either identified or assigned to families. Estimation of relative protein abundances revealed that venom is dominated by three-finger toxins (77.5%; including 24.3% cytotoxins and 53.2% neurotoxins) and phospholipases A 2 (13.5%). It also contains lower proportions of components belonging to nerve growth factor, ohanin/vespryn, cysteine-rich secretory protein, C-type lectin/lectin-like, nucleotidase, phosphodiesterase, metalloproteinase, l -amino acid oxidase, cobra venom factor, and cytidyltransferase protein families. Small amounts of three nucleosides were also evidenced: adenosine, guanosine, and inosine. The most relevant lethal components, categorized by means of a ‘toxicity score’, were α-neurotoxins, followed by cytotoxins/cardiotoxins. IgGs isolated from a person who had repeatedly self-immunized with a variety of snake venoms were immunoprofiled by ELISA against all venom fractions. Stronger responses against larger toxins, but lower against the most critical α-neurotoxins were obtained. As expected, no neutralization potential against N. kaouthia venom was therefore detected. Combined, our results display a high level of venom complexity, unveil the most relevant toxins to be neutralized, and provide prospects of discovering human IgGs with toxin neutralizing abilities through use of phage display screening. [ABSTRACT FROM AUTHOR]

On January 19th, 2021, Jesús María Jiménez-Porras, a pioneer in the study of snake venoms in Costa Rica, passed away. In the case of B. asper venom, further proteomic studies corroborated the findings of Jiménez-Porras and explored these phenomena for venom variability in more detail ([2]). Jiménez-Porras then studied the venoms of two Costa Rican viperid snake species, i.e., Bothrops atrox (now classified as B. asper) and Bothrops nummifer (now classified as Atropoides mexicanus) ([4], [5]). [Extracted from the article]

Snakebite envenoming is a common but neglected public health problem, particularly in impoverished rural regions of sub- Saharan Africa, Asia and Latin America. The only validated treatment for this condition is passive immunotherapy with safe and effective animal-derived antivenoms. However, there is a long-lasting crisis in the availability of these life-saving medications, particularly in sub- Saharan Africa and parts of Asia. We herein advocate a multicomponent strategy to substantially improve the availability of safe and effective antivenoms at the global level. This strategy is based on: (i) preparing validated collections of representative venom pools from the most medically dangerous snakes in high-risk regions of the world; (ii) strengthening the capacity of national antivenom manufacturing and quality control laboratories and their regulatory authorities and establishing new facilities in developing countries through technology transfer, as an integral part of efforts to develop their biological products industry; (iii) getting established laboratories to generate antivenoms for various regions of the world; and (iv) getting governments and relevant organizations to give snakebite envenoming due recognition within national and international public health policy frameworks. These ways of making antivenom available should be complemented by actions to improve health information systems, the accessibility of antivenoms, the training of medical and nursing staff, and community-based education. Such a multicomponent strategy involving stakeholders on many levels could help consolidate sustainable improvements in antivenom availability worldwide. [ABSTRACT FROM AUTHOR]

Abstract: Parenteral administration of animal-derived antivenoms constitutes the mainstay in the treatment of snakebite envenomings. Despite the fact that this therapy has been available for over a century, the detailed understanding of the neutralizing and immunoreactivity profiles of the majority of antivenoms is pending. Currently, a combination of preclinical neutralization tests and ‘antivenomics’, i.e. a proteomic-based assessment of antivenom immunoreactivity, provides a powerful analytical platform to investigate the preclinical efficacy of antivenoms. In this review, the studies performed on the polyvalent antivenom manufactured by Instituto Clodomiro Picado, Costa Rica, are summarized. This antivenom is prepared by immunizing horses with a mixture of the venoms of Bothrops asper, Crotalus simus and Lachesis stenophrys, and is used in Central America for the treatment of envenomings by viperid species. Overall, the antivenom shows a widespread pattern of immunological reactivity against homologous and heterologous venoms, which correlates with its ability to neutralize lethal, hemorrhagic, myotoxic, coagulant, defibrinogenating, phospholipase A2 and proteinase activities of viperid venoms. At the same time, antivenomics detected several venom components against which the antivenom shows only partial or negligible immunorecognition, such as low molecular mass vasoactive peptides, disintegrins, and some phospholipases A2, P-I metalloproteinases and serine proteinases. Such information can be used to design strategies for enhancing the antibody response of horses against poorly immunogenic, toxicologically-relevant venom components in order to further improve the efficacy of this antivenom. Biological significance: The timely parenteral administration of an appropriate antivenom remains, more than a century after the development of the first serum antivenimeux by Calmette and Phisalix and Bertrand, the only currently effective treatment for snakebite envenomings. A key technical issue in the generation of novel antivenoms is the design of optimized immunization venom mixtures that ensure that the resulting antidotes will be effective against the highest number of venoms from snakes of medical concern across the geographical range where they will be used. Antivenomics is a proteomics-based protocol developed to complement in vitro and in vivo standard preclinical tests in the qualitative and quantitative characterization of the immunological profile and the extent of cross-reactivity of antivenoms against homologous and heterologous venoms. Antivenomics is translational venomics. The combination of antivenomics and neutralization assays represents a powerful analytical platform to investigate the efficacy of antivenoms at the molecular and preclinical levels. This article is part of a Special Issue entitled: Proteomics of non-model organisms. [Copyright &y& Elsevier]

Highlights: [•] Analgesics tramadol and morphine were used in mice injected with Bothrops asper venom. [•] Analgesics did not alter the acute toxicity of B. asper venom in mice. [•] Precautionary (prophylactic) analgesia should be introduced routinely in Toxinology. [Copyright &y& Elsevier]

The direct estimate of 46,000 snakehite deaths in India in 2005(1 for every 2 lilY/AIDS deaths), based on verbal autopsies, renders unrealistic the total of only 47,000 snakebite deaths in the whole world in 2010, obtained indirectly as part of the "Global Burden of Disease 2010" study. Persistent underestimation of its true morbidity and mortality has made snakebite the most neglected of all the WHO's "neglected tropical diseases", downgrading its public health importance. Strategies to address this neglect should include the improvement of antivenom, the only specific antidote to envenoming. To accommodate increased understanding of geographical intraspecific variation in venom composition and the range of - snake species that are medically important in India, the design of antivenoms (choice of venom sources and species coverage) should be reconsidered. Methods of preclinical and clinical testing should be improved. The relatively new science of venomics involves techniques and strategies for assessing the toxin composition of snake venoms directly through proteomics-centred approaches or indirectly via high-throughput venom gland transcriptomics and bioinIormatic analysis. Antivenomics is translational venomics: a proteomics-based protocol to quantify the extent of cross-reactivity of antivenoms against homologous and heterologous venoms. These approaches could revolutionize the preclinical assessment of antivenom efficacy, leading to a new generation of antivenoms that are clinically more effective. [ABSTRACT FROM AUTHOR]

Abstract: The assessment of the capacity of antivenoms to neutralize the lethal activity of snake venoms is the gold standard in the preclinical analysis of antivenom efficacy, and is routinely performed by manufacturers and quality control laboratories. However, the complexity of snake venom composition and toxicological profile demands that, for many venoms, such as those of viperid snakes and some elapids, the neutralization of lethality be complemented with the analysis of the neutralization of other relevant toxic activities, such as hemorrhagic, myotoxic, necrotizing, procoagulant and defibrinogenating effects. This expanded protocol for preclinical testing of antivenoms should be used when a new antivenom is developed or when an existing antivenom is introduced in a new geographical setting for the neutralization of either homologous or heterologous venoms. In recent years, the assessment of the immunological reactivity of antivenoms has been enriched by the use of proteomic tools, with a methodology named ‘antivenomics’. This allows the identification of venom components to which antivenoms have, or lack, antibodies, and thus complements the data gathered in neutralization tests, paving the way for a knowledge-based improvement of antivenom design and efficacy. International projects involving participants of manufacturing, quality control and academic research groups should be promoted in order to gain a deeper understanding on the preclinical neutralizing spectrum of antivenoms. [Copyright &y& Elsevier]

Abstract: A polyspecific antivenom is used in Central America for the treatment of envenomings by viperid snakes. This antivenom is generated in horses hyperimmunized with a mixture of venoms from Bothrops asper, Crotalus simus and Lachesis stenophrys. The present study analyzed the ability of this antivenom to neutralize the venoms of three Central American viperid species of the ‘Porthidium group’, i.e. Porthidium nasutum, Porthidium ophryomegas and Cerrophidion sasai, formerly classified as Cerrophidion godmani. In addition, the immunorecognition of the components of these venoms was assessed by immunoaffinity antivenomics. The antivenom proved effective in neutralizing the lethal, hemorrhagic, myotoxic, phospholipase A2 (PLA2) and proteinase activities of the three venoms, albeit exhibiting quantitative differences in the values of the Median Effective Doses (ED50). Excepting for certain low molecular mass bands corresponding to disintegrins, and some PLA2s and PI-metalloproteinases, Western blotting and immunoaffinity chromatography revealed immunorecognition of most Porthidium and Cerrophidion venom proteins. In agreement with in vivo neutralization assays, immobilized antivenom IgGs showed higher immunocapturing activity of toxins from both Porthidium taxa than from C. sasai. Overall our results demonstrate a significant paraspecific protection of the Costa Rican polyspecific antivenom against the three venoms sampled. They also stress the need to search for novel ways to enhance the immune response of horses against several weakly immunogenic venom components. [Copyright &y& Elsevier]

Abstract: Phospholipases A2 (PLA2s) are abundant components of snake venoms, where they play toxic and digestive roles. Despite having a similar three-dimensional structure, venom PLA2s exert an amazing variety of toxic and pharmacological effects, which include neurotoxic, myotoxic, hemolytic, edematogenic, hyperalgesic, pro-inflammatory, hypotensive, platelet-aggregation inhibitory, anticoagulant, cytotoxic, and bactericidal activities. Toxinologists have made significant contributions to deciphering the structure, molecular evolution, mechanisms of action, receptors, role of enzymatic activity for toxicity, structural determinants of toxicity and selectivity, and the impact of these enzymes in the overall pathophysiology of snakebite envenoming. The present work highlights some of the most relevant contributions in the study of venom PLA2s, including the personal accounts of the authors of these studies. [Copyright &y& Elsevier]

A second generation antivenomics protocol, based on affinity chromatography, was compared with a previously (first generation) immunodepletion protocol using as a proof of principle the pan-African EchiTAb-Plus-ICP ® IgG antivenom and the venoms of Echis ocellatus , Bitis arietans , and African spitting cobras. The antivenom showed qualitatively similar immunoreactivity patterns using either antivenomic approach. Quantitative departures were noticed between both methods, which may be ascribed to differences in calculating the relative amounts of the non-recognized venom proteins. The smoother baseline in chromatograms of the affinity column allowed better resolution and more accurate quantification of the antivenomic outcome than the original immunodepletion protocol. Our results indicate that both methods can be used interchangeably to investigate the in vitro immunoreactivity of antivenoms. However, advantages of the second generation antivenomics are the possibility of analyzing F(ab′) 2 antivenoms and the reusability of the affinity columns. These features contribute to the generalization, economy and reproducibility of the method. [ABSTRACT FROM AUTHOR]

Snakebite envenomings constitute a serious and neglected public health problem. Despite the fact that effective treatment exists, i.e. administration of animal-derived antivenoms, the availability and accessibility of these life-saving immunobiologicals is deficitary in various parts of the world, particularly in sub-Saharan Africa and some regions of Asia. This article discusses some of the problems that need to be circumvented in order to improve the availability and accessibility of antivenoms. The conglomerate of antivenom manufacturers is highly heterogeneous in terms of technological base, qualification of staff, implementation of Good Manufacturing Practices (GMPs), and volume of production. Therefore, improvements in antivenom quality and availability should be based on strategies tailored to the situation of each region or country; in this context, three different scenarios are discussed. Accessibility of antivenoms demands concerted efforts at multiple levels, including raising the awareness of public health authorities on the relevance of the problem, implementing innovative antivenom purchasing schemes, strengthening national distribution channels on the basis of robust epidemiological information, improving the cold chain and the provision of health services in remote rural settings, supporting the correct use of antivenoms, and promoting the involvement of local community organizations in various aspects of prevention and management. These tasks should be envisaged in terms of synergistic, interprogrammatic and intersectorial interventions, with the participation of many players. [ABSTRACT FROM AUTHOR]

Abstract: Venoms of several Naja species found in Sub-Saharan Africa, and commonly known as "spitting cobras", induce a predominantly cytotoxic pattern of envenomings that may evolve into tissue necrosis and gangrene. Cytotoxic components of their venoms have been identified as members of the three-finger toxin and phospholipase A2 protein families. In this study, an in vitro assay using the myogenic cell line C2C12, was utilized to compare the cytolytic activities of venoms from five species of spitting cobras: Naja nigricollis, Naja katiensis, Naja pallida, Naja nubiae, and Naja mossambica. These venoms were strongly cytotoxic, causing a 50% effect at ∼1.5 μg/well (15 μg/ml), except for N. katiensis venom, which required nearly twice this amount. Using the cell-based assay, the ability of an equine polyspecific antivenom (EchiTab-Plus-ICP) to neutralize cytotoxicity was assessed. The antivenom completely inhibited the cytotoxic activity of all five venoms, although high antivenom/venom ratios were needed. Neutralization curves displayed the following decreasing order of efficiency: N. nubiae > N. pallida > N. mossambica > N. nigricollis > N. katiensis. Results indicate that neutralizing antibodies toward toxins responsible for this particular effect are present in the antivenom, albeit in low titers. Fucoidan, a natural sulfated polysaccharide known to inhibit the toxic effects of some basic snake venom components, was unable to reduce cytotoxicity of Naja venoms. Results emphasize the need of enhancing the immunogenicity of low molecular mass toxins during antivenom production, as well as to search for useful toxin inhibitors which could complement antivenom therapy. [Copyright &y& Elsevier]

Abstract: The development of snake antivenoms more than a century ago should have heralded effective treatment of the scourge of snakebite envenoming in impoverished, mostly rural populations around the world. That snakebite still exists today, as a widely untreated illness that maims, kills and terrifies men, women and children in vulnerable communities, is a cruel anachronism. Antivenom can be an effective, safe and affordable treatment for snakebites, but apathy, inaction and the politicisation of public health have marginalised both the problem (making snakebite arguably the most neglected of all neglected tropical diseases) and its solution. For lack of any coordinated approach, provision of antivenoms has been pushed off the public health agenda, leading to an incongruous decline in demand for these crucial antidotes, excused and fed by new priorities, an absence of epidemiological data, and a poor regulatory framework. These factors facilitated the infiltration of poor quality products that degrade user confidence and undermine legitimate producers. The result is that tens of thousands are denied an essential life-saving medicine, allowing a toll of human suffering that is a summation of many individual catastrophes. No strategy has been developed to address this problem and to overcome the intransigence and inaction responsible for the global tragedy of snakebite. Attempts to engage with the broader public health community through the World Health Organisation (WHO), GAVI, and other agencies have failed. Consequently, the toxinology community has taken on a leadership role in a new approach, the Global Snakebite Initiative, which seeks to mobilise the resources, skills and experience of scientists and clinicians for whom venoms, toxins, antivenoms, snakes and snakebites are already fields of interest. Proteomics is one such discipline, which has embraced the potential of using venoms in bio-discovery and systems biology. The fields of venomics and antivenomics have recently evolved from this discipline, offering fresh hope for the victims of snakebites by providing an exciting insight into the complexities, nature, fundamental properties and significance of venom constituents. Such a rational approach brings with it the potential to design new immunising mixtures from which to raise potent antivenoms with wider therapeutic ranges. This addresses a major practical limitation in antivenom use recognised since the beginning of the 20th century: the restriction of therapeutic effectiveness to the specific venom immunogen used in production. Antivenomic techniques enable the interactions between venoms and antivenoms to be examined in detail, and if combined with functional assays of specific activity and followed up by clinical trials of effectiveness and safety, can be powerful tools with which to evaluate the suitability of current and new antivenoms for meeting urgent regional needs. We propose two mechanisms through which the Global Snakebite Initiative might seek to end the antivenom drought in Africa and Asia: first by establishing a multidisciplinary, multicentre, international collaboration to evaluate currently available antivenoms against the venoms of medically important snakes from specific nations in Africa and Asia using a combination of proteomic, antivenomic and WHO-endorsed preclinical assessment protocols, to provide a validated evidence base for either recommending or rejecting individual products; and secondly by bringing the power of proteomics to bear on the design of new immunising mixtures to raise Pan-African and Pan-Asian polyvalent antivenoms of improved potency and quality. These products will be subject to rigorous clinical assessment. We propose radically to change the basis upon which antivenoms are produced and supplied for the developing world. Donor funding and strategic public health alliances will be sought to make it possible not only to sustain the financial viability of antivenom production partnerships, but also to ensure that patients are relieved of the costs of antivenom so that poverty is no longer a barrier to the treatment of this important, but grossly neglected public health emergency. [Copyright &y& Elsevier]

The article discusses the importance of developing local scientific communities in low- and middle-income countries (LMICs) to have a sustainable impact on public health. It focuses on the 10-year activities of the Network for Research and Training in Tropical Diseases in Central America (NeTropica), which aimed to develop a competitive scientific community in the field of tropical diseases in Central America. The article provides historical context on the challenges faced by Central America in the 1980s and the emergence of a graduate program between the Karolinska Institute and Central American universities. NeTropica aims to strengthen the Central American scientific community by providing research grants and promoting academic activities. It has seen an increase in interest from Central American scientists, resulting in a higher quality of selected projects. The program has supported regional graduate programs, organized scientific meetings and workshops, and generated scientific publications in well-recognized journals. However, it faces challenges due to limited research funds and the political and economic instability of the region. Despite these challenges, NeTropica has made significant contributions to public health and science in Central America. [Extracted from the article]

Abstract: The parenteral administration of antivenoms is the cornerstone of snakebite envenoming therapy. Efforts are made to ensure that antivenoms of adequate efficacy and safety are available world-wide. We address the main issues to be considered for the development and manufacture of improved antivenoms. Those include: (a) A knowledge-based composition design of venom mixtures used for immunization, based on biochemical, immunological, toxicological, taxonomic, clinical and epidemiological data; (b) a careful selection and adequate management of animals used for immunization; (c) well-designed immunization protocols; (d) sound innovations in plasma fractionation protocols to improve recovery, tolerability and stability of antivenoms; (e) the use of recombinant toxins as immunogens to generate antivenoms and the synthesis of engineered antibodies to substitute for animal-derived antivenoms; (f) scientific studies of the contribution of existing manufacturing steps to the inactivation or removal of viruses and other zoonotic pathogens; (g) the introduction of novel quality control tests; (h) the development of in vitro assays in substitution of in vivo tests to assess antivenom potency; and (i) scientifically-sound pre-clinical and clinical assessments of antivenoms. These tasks demand cooperative efforts at all main stages of antivenom development and production, and need concerted international partnerships between key stakeholders. [Copyright &y& Elsevier]

Abstract: In this study, the production of prostaglandin E2 (PGE2) and up-regulation in cyclooxygenase (COX) pathway induced by a phospholipase A2 (PLA2), myotoxin-III (MT-III), purified from Bothrops asper snake venom, in isolated neutrophils were investigated. The arachidonic acid (AA) production and the participation of intracellular PLA2s (cytosolic PLA2 and Ca2+-independent PLA2) in these events were also evaluated. MT-III induced COX-2, but not COX-1 gene and protein expression in neutrophils and increased PGE2 levels. Pretreatment of neutrophils with COX-2 and COX-1 inhibitors reduced PGE2 production induced by MT-III. Arachidonyl trifluoromethyl ketone (AACOCF3), an intracellular PLA2 inhibitor, but not bromoenol lactone (BEL), an iPLA2 inhibitor, suppressed the MT-III-induced AA and PGE2 release. In conclusion, MT-III directly stimulates neutrophils inducing COX-2 mRNA and protein expression followed by production of PGE2. COX-2 isoform is preeminent over COX-1 for production of PGE2 stimulated by MT-III. PGE2 and AA release by MT-III probably is related to cPLA2 activation. [Copyright &y& Elsevier]

Abstract: Snakebite envenoming is a neglected public health challenge of compelling importance in many regions of the world, particularly sub-Saharan Africa, Asia, Latin America and Papua-New Guinea. Addressing the problem of snakebite effectively demands an integrated multifocal approach, targeting complex problems and involving many participants. It must comprise: [(a)] Acquisition of reliable information on the incidence and mortality attributable to snakebite envenoming, and the number of people left with permanent sequelae. [(b)] Improvements in production of effective and safe antivenoms, through strategies aimed at strengthening the technological capacity of antivenom manufacturing laboratories. [(c)] Increasing the capacity of low-income countries to produce specific immunogens (snake venoms) locally, and to perform their own quality control of antivenoms. [(d)] Commitments from regional producers to manufacture antivenoms for countries where antivenom production is not currently feasible. [(e)] Implementation of financial initiatives guaranteeing the acquisition of adequate volumes of antivenom at affordable prices in low-income countries. [(f)] Performance of collaborative studies on the safety and effectiveness of antivenoms assessed preclinically and by properly designed clinical trials. [(g)] Development of antivenom distribution programmes tailored to the real needs and epidemiological situations of rural areas in each country. [(h)] Permanent training programmes for health staff, particularly in rural areas where snakebites are frequent. [(i)] Implementation of programmes to support those people whose snakebites resulted in chronic disabilities. [(j)] Preventive and educational programmes at the community level, with the active involvement of local organizations and employing modern methods of health promotion. Such an integrated approach, currently being fostered by the Global Snake Bite Initiative of the International Society on Toxinology and by the World Health Organization, will help to alleviate the enormous burden of human suffering inflicted by snakebite envenoming. [Copyright &y& Elsevier]

Abstract: Phospholipases A2 (PLA2) are major components of snake venoms, exerting a variety of relevant toxic actions such as neurotoxicity and myotoxicity, among others. Since the majority of toxic PLA2s are basic proteins, acidic isoforms and their possible roles in venoms are less understood. In this study, an acidic enzyme (BaspPLA2-II) was isolated from the venom of Bothrops asper (Pacific region of Costa Rica) and characterized. BaspPLA2-II is monomeric, with a mass of 14,212 ± 6 Da and a pI of 4.9. Its complete sequence of 124 amino acids was deduced through cDNA and protein sequencing, showing that it belongs to the Asp49 group of catalytically active enzymes. In vivo and in vitro assays demonstrated that BaspPLA2-II, in contrast to the basic Asp49 counterparts present in the same venom, lacks myotoxic, cytotoxic, and anticoagulant activities. BaspPLA2-II also differed from other acidic PLA2s described in Bothrops spp. venoms, as it did not show hypotensive and anti-platelet aggregation activities. Furthermore, this enzyme was not lethal to mice at intravenous doses up to 100 μg (5.9 μg/g), indicating its lack of neurotoxic activity. The only toxic effect recorded in vivo was a moderate induction of local edema. Therefore, the toxicological characteristics of BaspPLA2-II suggest that it does not play a key role in the pathophysiology of envenomings by B. asper, and that its purpose might be restricted to digestive functions. Immunochemical analyses using antibodies raised against BaspPLA2-II revealed that acidic and basic PLA2s form two different antigenic groups in B. asper venom. [Copyright &y& Elsevier]

Abstract: The study of snake venom-induced local tissue pathology has been predominantly based on experimental designs and concepts that view tissue alterations from a dichotomous, homogeneous and reductionist perspective. Experimental observations, however, indicate that cells and extracellular matrix are affected by venoms and toxins in a complex and heterogeneous fashion, and that the effect of whole venoms in whole organisms cannot be properly assessed by studying only the action of isolated toxins in isolated systems. It is proposed that a novel conceptual and methodological frame is necessary to better understand the complexity of these pathological alterations from a holistic, systems biology perspective. [Copyright &y& Elsevier]