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A 34-year-old man developed severe envenomation after being bitten by a Crotalus durissus (rattlesnake), which was treated with anticrotalic serum. Three weeks later, the patient reported paresthesia and neuropathic pain in the left hand, which had progressed to all four limbs. Electroneuromyography revealed asymmetric axonal sensorimotor multiple mononeuropathy. The patient was treated with prednisone, and six months later there was significant improvement in sensorimotor conduction. This is the first reported case of multiple mononeuropathy associated with C. durissus envenomation. Post-snake envenomation peripheral neuropathy is a rare complication requiring prompt recognition and treatment to optimize nerve function and enhance patient outcomes.

Introduction: Snakebite envenoming (SBE) results in over 500 000 deaths or disabling injuries annually. Varespladib methyl, an oral inhibitor of secretory phospholipase A2, is a nearly ubiquitous component of snake venoms. We conducted a phase II clinical trial to assess efficacy and safety of oral varespladib methyl in patients bitten by venomous snakes., Methods: This double-blind, randomised, placebo-controlled trial enrolled patients in emergency departments in India and the USA. Patients with SBE were randomly assigned (1:1) to receive varespladib methyl or placebo two times per day for 1 week. All patients received standard of care, including antivenom. The primary outcome was change in the composite Snakebite Severity Score (SSS) measuring the severity of envenoming, from baseline to the average composite SSS at 6 and 9 hours., Results: Among 95 patients randomised August 2021 through November 2022, the most common snakebites were from Russell's vipers (n=29), copperheads (n=18) and rattlesnakes (n=14). The SSS improved from baseline to the average at 6 and 9 hours by 1.1 (95% CI, 0.7 to 1.6) in the varespladib group versus 1.5 (95% CI, 1.0 to 2.0) in the placebo group (difference -0.4, 95% CI, -0.8 to 0.1, p=0.13). While key secondary outcomes were not statistically different by treatment group, benefit was seen in the prespecified subgroup initiating study drug within 5 hours of bite (n=37). For this early treatment group, clinically important differences were observed for illness severity over the first week, patient-reported function on days 3 and 7 and complete recovery. No death or treatment emergent serious adverse event occurred., Conclusion: For emergency department treatment of snakebites, the addition of varespladib to antivenom did not find evidence of difference for the primary outcome based on the SSS. A potentially promising signal of benefit was observed in patients initiating treatment within 5 hours of snakebite., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Variation in snake venoms is well documented, both between and within species, with intraspecific venom variation often correlated with geographically distinct populations. The puff adder, Bitis arietans, is widely distributed across sub-Saharan Africa and into the Arabian Peninsula where it is considered a leading cause of the ~310,000 annual snakebites across the region, with its venom capable of causing substantial morbidity and mortality. Despite its medical importance and wide geographic distribution, there is little known about venom variation between different B. arietans populations and the potential implications of this variation on antivenom efficacy., Methodology: We applied a range of analyses, including venom gland transcriptomics, in vitro enzymatic assays and reverse phase chromatography to comparatively analyse B. arietans venoms originating from Nigeria, Tanzania, and South Africa. Immunological assays and in vitro enzymatic neutralisation assays were then applied to investigate the impact of venom variation on the potential efficacy of three antivenom products; SAIMR Polyvalent, EchiTAb-Plus and Fav-Afrique., Findings: Through the first comparison of venom gland transcriptomes of B. arietans from three geographically distinct regions (Nigeria, Tanzania, and South Africa), we identified substantial variation in toxin expression. Findings of venom variation were further supported by chromatographic venom profiling, and the application of enzymatic assays to quantify the activity of three pathologically relevant toxin families. However, the use of western blotting, ELISA, and in vitro enzymatic inhibition assays revealed that variation within B. arietans venom does not appear to substantially impact upon the efficacy of three African polyvalent antivenoms., Conclusions: The large distribution and medical importance of B. arietans makes this species ideal for understanding venom variation and the impact this has on therapeutic efficacy. The findings in this study highlight the likelihood for considerable venom toxin variation across the range of B. arietans, but that this may not dramatically impact upon the utility of treatment available in the region., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dawson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cerebral sinus venous thrombosis (CSVT) is an uncommon and potentially life-threatening neurological disorder that is often missed because its clinical and radiological symptoms are not specific. Snake bites are a rare cause of cerebral venous sinus thrombosis that must be recognized and treated promptly to improve survival. Here, we present a case of a 30-year-old male patient who had cerebral venous thrombosis after snake bite in the rural area of southern Somalia. After close monitoring with anticoagulation, the condition of the patient improved and discharged from the hospital with full of consciousness. There are only a few cases reported in the literature of snake bites causing cerebral venous thrombosis., Competing Interests: The authors have no conflicts of interest., (© 2024 Sidow et al.)

Snakebite envenoming (SBE) remains a severely neglected public health issue, particularly affecting tropical and subtropical regions, with Africa experiencing an estimated 435,000 to 580,000 snakebites annually, leading to high morbidity and mortality rates, especially across Africa and Asia. Recognized as a Neglected Tropical Disease, SBE management is further complicated by the inadequate efficacy of current antivenom treatments. Of particular concern are cobras ( Naja sp.), whose neurotoxins can induce rapid fatal respiratory paralysis. In this study, we investigate the potential of nanobodies as a promising next-generation of immunotherapeutics against cobra venoms. Through a dual strategy of the characterization of venom toxic fractions from cobras captured for the first time in Algeria and Tunisia biotopes, coupled with in vitro assays to evaluate their interactions with acetylcholine receptors, and subsequent immunization of dromedaries to produce specific nanobodies, we identified two lethal fractions, F5 and F6, from each venom, and selected five nanobodies with significant binding and neutralizing of 3DL50 (0.74 mg/kg). The combination of these nanobodies demonstrated a synergistic effect, reaching 100% neutralizing efficacy of 2DL50 lethal venom fraction (0.88 mg/kg) doses in mice. Additionally, our findings highlighted the complex mechanism of cobra venom action through the lethal synergism among its major toxins.

We present a case of neurotoxic effects in a pediatric patient after envenomation by a timber rattlesnake ( Crotalus horridus ) in the Appalachian upstate of South Carolina. Though some members of this species are capable of primarily neurotoxic envenomation, there is heterogeneity in venom composition, and neurotoxic timber rattlesnakes are not endemic to the Appalachian region. However, neurotoxic effects caused by C horridus species lacking typical neurotoxins have been suspected, though not previously confirmed in the medical literature. This case presents a patient who was envenomated by a genotypically confirmed non-neurotoxic C horridus but who nevertheless presented with symptoms consistent with primary neurotoxicity. Neurotoxic effects can be variable in their response to traditional antivenom, though this patient demonstrated rapid response to treatment, representing a novel case in the literature of neurotoxic effects from a snake lacking typical neurotoxins with documented improvement with traditional antivenom.

Background: Snakebite is a global environmental and occupational hazard and a significant public health threat. In rural areas, snakebite cases often go unreported and undocumented due to the lack of access to well-structured healthcare facilities/infrastructure. In some cases, the need for antisnake venom (ASV) far outstrips supply, negatively affecting treatment outcomes. This study, therefore, assessed the epidemiological characteristics of snakebite cases, their management, and how antivenoms are utilised at the selected hospital in the Jasikan District Hospital. Methods: A 6-year retrospective study using secondary data from antivenom return forms (pharmacy records), clinical records (patient folders), the District Health Information Management System-2 (DHIMS-2) database, and consulting room registers was carried out in selected hospitals in the Jasikan District, Oti, Ghana. Results: The predominant symptom of snakebite was localised pain (71.4%). The snakebite commonly occurred at home (19%) and on farms (18%). Of the 98 snakebite cases, ASV was administered to 73 (74.5%) cases. Supportive treatment applied included prophylactic antitetanus immunoglobulin (ATS) (80.6%), prophylactic antibiotics (63%), corticosteroids (80.6%), and analgesics (63%). 95% ( n = 94) of complete recoveries were recorded; three were discharged against medical advice, and one was mortality. The supply and use of antivenom were erratic throughout the months of high incidence, partly due to inconsistent availability at the Regional Medical Stores. The average ASV vials and hospital stay duration were 1.23 ± 0.86 vials and 2.67 ± 1.97 days, respectively. Although the peak of snakebites occurs in April, May, and June, the demand for antivenom in April and May exceeded supply. Conclusion: The outcome of most snakebite case management was appropriate, irrespective of inadequate ASV supply in certain months. The erratic antivenom supply should be aligned with seasonal and facility-use patterns to enhance regional snakebite management., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Courage Edem Ketor et al.)

Background: Snake bites cause considerable morbidity and mortality worldwide, yet evidence from low- and middle-income countries remains fragmented. This is particularly the case in Eastern Mediterranean Region where available data on snake bites is relatively weak. Without reliable data, it is difficult to make the case for greater visibility and investment to address the snakebite burden in this Region. A scoping review was therefore conducted to summarize evidence on snake bites in countries of the Eastern Mediterranean., Methodology/principal Findings: The review employed manual and electronic searching methods of four databases plus Google Scholar, ultimately including 196 records from 20 countries published between 2000 and 2023. More than half originated from Iran, Morocco, and Pakistan. Many records lacked information on permanent sequalae, disability, snake species, and types and sources of antivenoms. When identified, offending snakes belonged to 30 species. Use of more than 12 types of antivenoms were described across the Region, and some were not specific to indigenous species., Conclusion/significance: Despite the relatively large number of publications identified, the data were concentrated in just a few countries in the Region, and there was little or no information available for the remainder. As is the case worldwide, disability associated with snake bites was poorly characterized and quantified across the Region. There is an urgent need for concrete action at national and regional levels to enhance epidemiological surveillance, research, and the collection of clinical, disability and outcomes data to inform policy and public health investment. Greater regional cooperation and collaboration is also crucial for addressing this neglected disease throughout the Region., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 World Health Organization. Licensee Public Library of Science. This is an open access article distributed under the Creative Commons Attribution IGO License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/3.0/igo/. In any use of this article, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article’s original URL.)

Snakebite envenomation remains an important, yet a neglected public health issue in most tropical and subtropical countries. Underdeveloped medical infrastructure, suboptimal medical services, poor documentation and failure to make snake-related injury a mandatory notifiable disease are important contributing factors. The King Cobra (Ophiophagus hannah) is a medically significant species encountered in Malaysia however, there have been few publications from the clinical perspective. The objectives of this study were to determine the frequency of King Cobra related injuries, geographical distribution, clinical presentation, type and frequency of antivenom utilization and the management outcome. This is a cross-sectional study of confirmed King Cobra related injuries consulted to Remote Envenomation Consultation Services (RECS) from 2015 to 2020. Data were extracted from the RECS database and descriptively analyzed. A total of 32 cases of King Cobra bite were identified. Most cases were from Peninsular Malaysia with the most frequent from the state of Pahang (n = 9, 28.1%). Most patients got bitten while attempting to catch or play with the snake (68.8%). Signs and symptoms of envenomation were documented in 24 (75.0%) cases and the most frequent systemic manifestation was ptosis (n = 13, 40.6%). Tracheal intubation and ventilatory support were required in 13 (40.6%) patients. Antivenom was administered to 22 (68.8%) patients with most (25.0%) receiving 10 vials (1 dose). The commonest antivenom used was monospecific King Cobra antivenom (50.0%) from Thai Red Cross. There was one death documented due to complications from necrotizing fasciitis and septicemia. Public awareness of the dangers and proper handling of King Cobras needs to be emphasised. Timely administration of the appropriate antivenom is the definitive treatment and leads to favorable outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Renault et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Access to antivenoms in cases of snakebite continues to be an important public health issue around the world, especially in rural areas with poorly developed health care systems. This study aims to evaluate therapeutic itineraries and antivenom accessibility following snakebites in the states of Oaxaca and Chiapas in southern Mexico. Employing an intercultural health approach that seeks to understand and bridge allopathic and traditional medical perceptions and practices, we conducted field interviews with 47 snakebite victims, documenting the therapeutic itineraries of 54 separate snakebite incidents that occurred between 1977 and 2023. Most victims used traditional remedies as a first line of treatment, often to withstand the rigors of a long journey to find antivenoms. The main obstacles to antivenom access were distance, poor antivenom availability, and cost. Standard antivenom treatment is highly valued and sought after, even as traditional beliefs and practices persist within a cultural framework known as the "hot-cold" system. The findings are crucial for informing future enhancements to antivenom distribution systems, health education initiatives, and other interventions aimed at mitigating the impact of snakebites in the region., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Vasquez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Local tissue destruction following envenomation from North American snakes, particularly those within the Crotalinae subfamily, has the potential to progress to compartment syndrome. The pathophysiology of venom-induced compartment syndrome (VICS) is a debated topic and is distinct from trauma/reperfusion-induced compartment syndrome. Heterogeneity exists in the treatment practices of VICS, particularly regarding the decision to progress to fasciotomy. Associations with functional outcomes and evolution in clinical practice since the introduction of Crotalidae polyvalent immune Fab (FabAV) have not been well defined. Our goal was to identify the potential gaps in the literature regarding this phenomenon, as well as illuminate salient themes in the clinical characteristics and treatment practices of VICS., Methods: We conducted this systematic scoping-style review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Records were included if they contained data surrounding the envenomation and hospital course of one or more patients who were envenomated by a snake species native to North America and were diagnosed with compartment syndrome from 1980-2020., Results: We included 19 papers: 10 single- or two-patient case reports encompassing 12 patients, and nine chart reviews providing summary statistics of the included patients. In case reports, the median compartment pressure when reported was 60 millimeters of mercury (interquartile range 55-68), 66% underwent fasciotomy, and functional outcomes varied. Use of antivenom appeared to be more liberal with FabAV than the earlier antivenin Crotalidae polyvalent. Rapid progression of swelling was the most commonly reported symptom. Among the included retrospective chart reviews, important data such as compartment pressures, consistent laboratory values, and snake species was inconsistently reported., Conclusions: Venom-induced compartment syndrome is relatively rare. Existing papers generally describe good outcomes even in the absence of surgical management. Significant gaps in the literature regarding antivenom dosing practices, serial compartment pressure measurements, and functional outcomes highlight the need for prospective studies and consistent standardized reporting., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.

Eastern Diamondback Rattlesnake ( Crotalus adamanteus ) envenomation is a medical emergency encountered in the Southeastern United States. The venom contains a snake venom thrombin-like enzyme (SVTLE) that is defibrinogenating, causing coagulopathy without effects on platelets in humans. This investigation utilized thrombelastographic methods to document this coagulopathy kinetically on the molecular level in a rabbit model of envenomation via the analyses of whole blood samples without and with platelet inhibition. Subsequently, the administration of a novel ruthenium compound containing site-directed antivenom abrogated the coagulopathic effects of envenomation in whole blood without platelet inhibition and significantly diminished loss of coagulation in platelet-inhibited samples. This investigation provides coagulation kinetic insights into the molecular interactions and results of SVTLE on fibrinogen-dependent coagulation and confirmation of the efficacy of a ruthenium antivenom. These results serve as a rationale to investigate the coagulopathic effects of other venoms with this model and assess the efficacy of this site-directed antivenom.

Snakebite envenomation is a major public health issue which causes severe morbidity and mortality, affecting millions of people annually. Of a diverse range of clinical manifestations, local and systemic haemorrhage are of particular relevance, as this may result in ischemia, organ failure and even cardiovascular shock. Thus far, in vitro studies have failed to recapitulate the haemorrhagic effects observed in vivo. Here, we present an organ-on-a-chip approach to investigate the effects of four different snake venoms on a perfused microfluidic blood vessel model. We assess the effect of the venoms of four snake species on epithelial barrier function, cell viability, and contraction/delamination. Our findings reveal two different mechanisms by which the microvasculature is being affected, either by disruption of the endothelial cell membrane or by delamination of the endothelial cell monolayer from its matrix. The use of our blood vessel model may shed light on the key mechanisms by which tissue-damaging venoms exert their effects on the capillary vessels, which could be helpful for the development of effective treatments against snakebites., (© 2024. The Author(s).)

The genus Vipera encompasses most species of medically significant venomous snakes of Europe, with Italy harbouring four of them. Envenomation by European vipers can result in severe consequences, but underreporting and the absence of standardised clinical protocols hinder effective snakebite management. This study provides an updated, detailed set of guidelines for the management and treatment of Vipera snakebite tailored for Italian clinicians. It includes taxonomic keys for snake identification, insights into viper venom composition, and recommendations for clinical management. Emphasis is placed on quick and reliable identification of medically relevant snake species, along with appropriate first aid measures. Criteria for antivenom administration are outlined, as well as indications on managing potential side effects. While the protocol is specific to Italy, its methodology can potentially be adapted for other European countries, depending on local resources. The promotion of comprehensive data collection and collaboration among Poison Control Centres is advocated to optimise envenomation management protocols and improve the reporting of epidemiological data concerning snakebite at the country level.

This retrospective, observational study describes the clinical findings, case management trends, and outcomes of 83 dogs and nine cats exposed to eastern coral snakes in a university teaching hospital setting. The medical records of dogs and cats that received antivenom following coral snake exposure were reviewed. Data collected included signalment, time to antivenom administration, physical and laboratory characteristics at presentation, clinical course during hospitalization, length of hospitalization, and survival to discharge. The mean time from presentation to coral snake antivenom administration was 2.26 ± 1.46 h. Excluding cases where the owner declined in-hospital care, the mean hospitalization time for dogs and cats was 50.8 h and 34 h, respectively. The mean number of antivenom vials was 1.29 (1-4). Gastrointestinal signs (vomiting and ptyalism) occurred in 42.2% (35/83) of dogs and 33.3% (3/9) of cats. Peripheral neurologic system deficits (ataxia, paresis to plegia, absent reflexes, and hypoventilation) were noted in 19.6% (18/92) of dogs and cats. Hemolysis was also common in 37.9% (25/66) of dogs but was not observed in cats. Mechanical ventilation (MV) was indicated in 12% (10/83) of dogs but no cats. Acute kidney injury (AKI), while rare, was a common cause of euthanasia at 20% (2/5) and was the most common complication during MV at 44.4% (4/9). Pigmenturia/hemolysis occurred in 88.9% (8/9) of MV cases and in all cases with AKI. Despite delays in antivenom administration by several hours, dogs and cats with coral snake exposure have low mortality rates (6% of dogs (5/83) and 0% of cats). Gastrointestinal signs were common but were not predictive of progression to neurological signs. Thus, differentiating between coral snake exposure and envenomation before the onset of neurological signs remains challenging.

Snakebite envenoming and its resulting complications are serious threats to the health of vulnerable people living in rural areas of developing countries. The knowledge of the heterogeneity of symptoms associated with snakebite envenoming and their management strategies is vital to treat such life-threatening complications to save lives. Russell's viper envenomation induces a diverse range of clinical manifestations from commonly recognised haemotoxic and local effects to several rare conditions that are often not reported. The lack of awareness about these unusual manifestations can affect prompt diagnosis, appropriate therapeutic approaches, and positive outcomes for patients. Here, we report pulmonary thromboembolism that developed in three patients following Russell's viper envenomation and demonstrate their common clinical features and diagnostic and therapeutic approaches used. All patients showed clinical signs of local (oedema) and systemic (blood coagulation disturbances) envenomation, which were treated using polyvalent antivenom. They exhibited elevated heart rates, breathlessness, and reduced oxygen saturation, which are non-specific but core parameters in the diagnosis of pulmonary embolism. The recognition of pulmonary embolism was also achieved by an electrocardiogram, which showed sinus tachycardia and computed tomography and echocardiogram scans further confirmed this condition. Anti-coagulant treatment using low-molecular-weight heparin offered clinical benefits in these patients. In summary, this report reinforces the broad spectrum of previously unreported consequences of Russell's viper envenomation. The constant updating of healthcare professionals and the dissemination of major lessons learned in the clinical management of snakebite envenoming through scientific documentation and educational programs are necessary to mitigate the adverse impacts of venomous snakebites in vulnerable communities.

Background: Each year, 3,800 cases of snakebite envenomation are reported in Mexico, resulting in 35 fatalities. The only scientifically validated treatment for snakebites in Mexico is the use of antivenoms. Currently, two antivenoms are available in the market, with one in the developmental phase. These antivenoms, produced in horses, consist of F(ab')2 fragments generated using venoms from various species as immunogens. While previous studies primarily focused on neutralizing the venom of the Crotalus species, our study aims to assess the neutralization capacity of different antivenom batches against pit vipers from various genera in Mexico., Methodology: We conducted various biological and biochemical tests to characterize the venoms. Additionally, we performed neutralization tests using all three antivenoms to evaluate their effectiveness against lethal activity and their ability to neutralize proteolytic and fibrinogenolytic activities., Results: Our results reveal significant differences in protein content and neutralizing capacity among different antivenoms and even between different batches of the same product. Notably, the venom of Crotalus atrox is poorly neutralized by all evaluated batches despite being the primary cause of envenomation in the country's northern region. Furthermore, even at the highest tested concentrations, no antivenom could neutralize the lethality of Metlapilcoatlus nummifer and Porthidium yucatanicum venoms. These findings highlight crucial areas for improving existing antivenoms and developing new products., Conclusion: Our research reveals variations in protein content and neutralizing potency among antivenoms, emphasizing the need for consistency in venom characteristics as immunogens. While Birmex neutralizes more LD50 per vial, Antivipmyn excels in specific neutralization. The inability of antivenoms to neutralize certain venoms, especially M. nummifer and P. yucatanicum, highlights crucial improvement opportunities, given the medical significance of these species., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Guadarrama-Martínez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Since around 100 years ago, the best treatment for millions of global snakebite victims has been polyclonal antivenoms. However, common antivenoms need continuous improvement to reduce rare, their side effects and get better performance. In the present study, Fab antivenom was produced through papain digestion of anti-cobra venom plasma, multi-step purification, and optimization, including ammonium sulfate precipitation and DEAE-cellulose column chromatography. Then, the existence of the corresponding Fab fragment antibody was seen and confirmed by SDS-PAGE method and double immunodifusion (Ouchterlony) test. In addition, the potency test in NIH laboratory mice revealed that each milliliter of the new Fab antivenom was able to neutralize 624 micrograms and (80LD 50 ) of cobra venom, which is about 15% more efficient than the primary plasma of the same concentration, and 1.57 times more effective than the cobra antivenom found in commercial hexavalent antivenom of Razi Institute. According to the findings, it seems that this new Fab antivenom can be used as a new candidate for treatment of cobra snakebite victims., Competing Interests: The authors declare that they have no conflict of interest.

Green pit viper bites induce mild toxicity with painful local swelling, blistering, cellulitis, necrosis, ecchymosis and consumptive coagulopathy. Several bite cases of green pit vipers have been reported in several south-east Asian countries including the north-eastern region of India. The present study describes isolation and characterization of a haemostatically active protein from Trimeresurus erythrurus venom responsible for coagulopathy. Using a two-step chromatographic method, a snake venom serine protease erythrofibrase was purified to homogeneity. SDS-PAGE of erythrofibrase showed a single band of ~30 kDa in both reducing and non-reducing conditions. The primary structure of erythrofibrase was determined by ESI LC-MS/MS, and the partial sequence obtained showed 77% sequence similarity with other snake venom thrombin-like enzymes (SVTLEs). The partial sequence obtained had the typical 12 conserved cysteine residues, as well as the active site residues (His57, Asp102 and Ser195). Functionally, erythrofibrase showed direct fibrinogenolytic activity by degrading the Aα chain of bovine fibrinogen at a slow rate, which might be responsible for causing hypofibrinogenemia and incoagulable blood for several days in envenomated patients. Moreover, the inability of Indian polyvalent antivenom (manufactured by Premium Serum Pvt. Ltd., Maharashtra, India) to neutralize the thrombin-like and plasmin-like activity of erythrofibrase can be correlated with the clinical inefficacy of antivenom therapy. This is the first study reporting an α-fibrinogenase enzyme erythrofibrase from T. erythrurus venom, which is crucial for the pathophysiological manifestations observed in envenomated victims.

Over 32,000 individuals succumb to snake envenoming in sub-Saharan Africa (sSA) annually. This results from several factors, including a lack of antivenom products capable of neutralising the venoms of diverse snake species in this region. Most manufacturers produce polyvalent antivenoms targeting 3 to 16 clinically important snake species in sSA. However, specific products are unavailable for many others, especially those with a restricted geographic distribution. While next-generation antivenoms, comprising a cocktail of broadly neutralising antibodies, may offer an effective solution to this problem, given the need for their clinical validation, recombinant antivenoms are far from being available to snakebite victims. One of the strategies that could immediately address this issue involves harnessing the cross-neutralisation potential of existing products. Therefore, we assessed the neutralisation potency of PANAF-Premium antivenom towards the venoms of 14 medically important snakes from 13 countries across sSA for which specific antivenom products are unavailable. Preclinical assays in a murine model of snake envenoming revealed that the venoms of most snake species under investigation were effectively neutralised by this antivenom. Thus, this finding highlights the potential use of PANAF-Premium antivenom in treating bites from diverse snakes across sSA and the utility of harnessing the cross-neutralisation potential of antivenoms.

Competing Interests: The authors have declared that no competing interests exist.

In Colombia, Micrurus snakebites are classified as severe according to the national clinical care guidelines and must be treated with specific antivenoms. Unfortunately, these types of antivenoms are scarce in certain areas of the country and are currently reported as an unavailable vital medicine. To address this issue, La Universidad de Antioquia, through its spin-off Tech Life Saving, is leading a project to develop third-generation polyvalent freeze-dried antivenom. The goal is to ensure access to this therapy, especially in rural and dispersed areas. This project aims to evaluate the physicochemical and preclinical parameters (standard quality characteristics) of a lab-scale anti-elapid antivenom batch. The antivenom is challenged against the venoms of several Micrurus species, including M. mipartitus , M. dumerilii , M. ancoralis , M. dissoleucus , M. lemniscatus , M. medemi , M. spixii , M. surinamensis , and M. isozonus , following the standard quality characteristics set by the World Health Organization (WHO). The antivenom demonstrates an appearance consistent with standards, 100% solubility within 4 min and 25 s, an extractable volume of 10.39 mL, a pH of 6.04, an albumin concentration of 0.377 mg/mL (equivalent to 1.22% of total protein), and a protein concentration of 30.97 mg/mL. Importantly, it maintains full integrity of its F(ab') 2 fragments and exhibits purity over 98.5%. Furthermore, in mice toxicity evaluations, doses up to 15 mg/mouse show no toxic effects. The antivenom also demonstrates a significant recognition pattern against Micrurus venoms rich in phospholipase A 2 (PLA 2 ) content, as observed in M. dumerilii , M. dissoleucus , and M. isozonus . The effective dose 50 (ED 50 ) indicates that a single vial (10 mL) can neutralize 2.33 mg of M. mipartitus venom and 3.99 mg of M. dumerilii venom. This new anti-elapid third-generation polyvalent and freeze-dried antivenom meets the physicochemical parameters set by the WHO and the regulators in Colombia. It demonstrates significant efficacy in neutralizing the venom of the most epidemiologically important Micrurus species in Colombia. Additionally, it recognizes seven other species of Micrurus venom with a higher affinity for venoms exhibiting PLA 2 toxins. Fulfilling these parameters represents the first step toward proposing a new pharmacological alternative for treating snakebites in Colombia, particularly in dispersed rural areas, given that this antivenom is formulated as a freeze-dried product.

Jatropha mollissima (Pohl) Baill. (Euphorbiaceae) is widely used in traditional medicine to treat inflammatory disorders. So, a topical gel containing the hydroethanolic extract of its leaves was developed and evaluated for its anti-inflammatory, wound healing, and antiophidic properties in mice. First, the chemical profile of different parts of the plant was characterized by liquid chromatography coupled to mass spectrometry (LC-MS) using molecular networking. In the leaf extract, 11 compounds were characterized, with a particular emphasis on the identification of flavonoids. The gel efficiently inhibited carrageenan-induced paw edema, as well as acute and chronic croton oil-induced ear edema models, thereby reducing inflammatory and oxidative parameters in inflamed tissues. Besides anti-inflammatory activity, the herbal gel showed significant wound healing activity. The edematogenic, hemorrhagic and dermonecrotic activities induced by Bothrops jararaca snake venom were effectively inhibited by the treatment with J. mollissima gel. The association with the herbal gel improved in up to 90% the efficacy of commercial snake antivenom in reduce venom-induced edema. Additionally, while antivenom was not able to inhibit venom-induced dermonecrosis, treatment with herbal gel reduced in 55% the dermonocrotic halo produced. These results demonstrate the pharmacological potential of the herbal gel containing J. mollissima extract, which could be a strong candidate for the development of herbal products that can be used to complement the current antivenom therapy against snake venom local toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Snakebite envenomation is a significant global health issue that requires specific antivenom treatments. In Taiwan, available antivenoms target a variety of snakes, but none specifically target Trimeresurus gracilis, an endemic and protected species found in the high mountain areas of Taiwan. This study evaluated the effectiveness of existing antivenoms against T. gracilis venom, focusing on a bivalent antivenom developed for Trimeresurus stejnegeri and Protobothrops mucrosquamatus (TsPmAV), as well as monovalent antivenoms for Deinagkistrodon acutus (DaAV) and Gloydius brevicaudus (GbAV). Our research involved in vivo toxicity testing in mice and in vitro immunobinding experiments using (chaotropic) enzyme-linked immunosorbent assays, comparing venoms from four pit viper species (T. gracilis, T. stejnegeri, P. mucrosquamatus, and D. acutus) with three types of antivenoms. These findings indicate that TsPmAV partially neutralized T. gracilis venom, marginally surpassing the efficacy of DaAV. In vitro tests revealed that GbAV displayed higher binding capacities toward T. gracilis venom than TsPmAV or DaAV. Comparisons of electrophoretic profiles also reveal that T. gracilis venom has fewer snake venom C-type lectin like proteins than D. acutus, and has more P-I snake venom metalloproteases or fewer phospholipase A2 than G. brevicaudus, T. stejnegeri, or P. mucrosquamatus. This study highlights the need for antivenoms that specifically target T. gracilis, as current treatments using TsPmAV show limited effectiveness in neutralizing local effects in patients. These findings provide crucial insights into clinical treatment protocols and contribute to the understanding of the evolutionary adaptation of snake venom, aiding in the development of more effective antivenoms for human health., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chuang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Snakebite envenoming is an important public health issue responsible for mortality and severe morbidity. Where mortality is mainly caused by venom toxins that induce cardiovascular disturbances, neurotoxicity, and acute kidney injury, morbidity is caused by toxins that directly or indirectly destroy cells and degrade the extracellular matrix. These are referred to as 'tissue-damaging toxins' and have previously been classified in various ways, most of which are based on the tissues being affected (e.g., cardiotoxins, myotoxins). This categorisation, however, is primarily phenomenological and not mechanistic. In this review, we propose an alternative way of classifying cytotoxins based on their mechanistic effects rather than using a description that is organ- or tissue-based. The mechanisms of toxin-induced tissue damage and their clinical implications are discussed. This review contributes to our understanding of fundamental biological processes associated with snakebite envenoming, which may pave the way for a knowledge-based search for novel therapeutic options., (© 2024. The Author(s).)

Snakebite envenomation (SBE) is a public health issue in sub-Saharan countries. Antivenom is the only etiological treatment. Excellent tolerance is essential in managing SBE successfully. This study aimed to evaluate tolerance of Inoserp TM PAN-AFRICA (IPA). It was conducted on fourteen sites across Cameroon. IPA was administered intravenously and repeated at the same dose every two hours if needed. Early and late tolerance was assessed by the onset of clinical signs within two hours and at a visit two weeks or more after the first IPA administration, respectively. Over 20 months, 447 patients presenting with a snakebite were included. One dose of IPA was administered to 361 patients and repeated at least once in 106 patients. No significant difference was shown between the proportion of adverse events in patients who received IPA (266/361, 73.7%) and those who did not (69/85, 81.2%) ( p = 0.95). Adverse reactions, probably attributable to IPA, were identified in four (1.1%) patients, including one severe (angioedema) and three mild. All these reactions resolved favorably. None of the serious adverse events observed in twelve patients were attributed to IPA. No signs of late intolerance were observed in 302 patients. Tolerance appears to be satisfactory. The availability of effective and well-tolerated antivenoms would reduce the duration of treatment and prevent most disabilities and/or deaths.

On the 26 th January 2023, a free to attend, 'improving in vivo snake venom research: a community discussion' meeting was held virtually. This webinar brought together researchers from around the world to discuss current neutralisation of venom lethality mouse assays that are used globally to assess the efficacy of therapies for snakebite envenoming. The assay's strengths and weaknesses were highlighted, and we discussed what improvements could be made to refine and reduce animal testing, whilst supporting preclinical antivenom and drug discovery for snakebite envenoming. This report summarises the issues highlighted, the discussions held, with additional commentary on key perspectives provided by the authors., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Marriott AE et al.)

Introduction: Antivenom is a lifesaving medicine for treating snakebite envenoming, yet there has been a crisis in antivenom supply for many decades. Despite this, substantial quantities of antivenom stocks expire before use. This study has investigated whether expired antivenoms retain preclinical quality and efficacy, with the rationale that they could be used in emergency situations when in-date antivenom is unavailable., Methods: Using WHO guidelines and industry test requirements, we examined the in vitro stability and murine in vivo efficacy of eight batches of the sub-Saharan African antivenom, South African Institute for Medical Research polyvalent, that had expired at various times over a period of 30 years., Results: We demonstrate modest declines in immunochemical stability, with antivenoms older than 25 years having high levels of turbidity. In vitro preclinical analysis demonstrated all expired antivenoms retained immunological recognition of venom antigens and the ability to inhibit key toxin families. All expired antivenoms retained comparable in vivo preclinical efficacy in preventing the lethal effects of envenoming in mice versus three regionally and medically important venoms., Conclusions: This study provides strong rationale for stakeholders, including manufacturers, regulators and health authorities, to explore the use of expired antivenom more broadly, to aid in alleviating critical shortages in antivenom supply in the short term and the extension of antivenom shelf life in the longer term., Competing Interests: Competing interests: GS, GD, AS, MV and GL are all employees of Instituto Clodomiro Picado, University of Costa Rica, a public manufacturer of antivenom products, including for sub-Saharan Africa., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Snakebite is a significant public health issue in which venom-induced consumption coagulopathy is a common and serious complication that results from the activation of the coagulation pathway by snake toxins. We report a male patient, 56 y old, who was thought to have been bitten by a snake on his left foot. He was transported to a nearby hospital where he received analgesics and 3 snake polyvalent antivenom vials, and then he was transported to our hospital after 12 h. He presented with 2 small puncture wounds, pain, blistering, and edema of the left foot. On the 2nd day, the patient developed gingival bleeding and hematuria. Laboratory investigations upon admission revealed prothrombin time (PT) of more than 3 min, prothrombin concentration (PC) of less than 2.5%, and an international normalized ratio (INR) of 23.43. Further investigation of urine showed more than 100 RBCs. Despite receiving 16 packs of plasma and 40 snake polyvalent antivenom vials manufactured by VACSERA over 3 days, hemoglobin concentration and platelet count decreased with the appearance of jaundice, lactate dehydrogenase was 520, and reticulocytes were 3.5%. PT was more than 300 s, and INR was still over range. Plasmapheresis and corticosteroids were provided, which improved the patient's general condition, PT, PC, and INR, and the patient was discharged after 6 days of hospital stay. This case report indicated that plasmapheresis and corticosteroids were clinically efficient approaches in the management of snake envenomation unresponsive to antivenom.

Local tissue damage following snakebite envenoming remains a poorly researched area. To develop better strategies to treat snakebites, it is critical to understand the mechanisms through which venom toxins induce envenomation effects including local tissue damage. Here, we demonstrate how the venoms of two medically important Indian snakes (Russell's viper and cobra) affect human skeletal muscle using a cultured human myoblast cell line. The data suggest that both venoms affect the viability of myoblasts. Russell's viper venom reduced the total number of cells, their migration, and the area of focal adhesions. It also suppressed myogenic differentiation and induced muscle atrophy. While cobra venom decreased the viability, it did not largely affect cell migration and focal adhesions. Cobra venom affected the formation of myotubes and induced atrophy. Cobra venom-induced atrophy could not be reversed by small molecule inhibitors such as varespladib (a phospholipase A 2 inhibitor) and prinomastat (a metalloprotease inhibitor), and soluble activin type IIb receptor (a molecule used to promote regeneration of skeletal muscle), although the antivenom (raised against the Indian 'Big Four' snakes) has attenuated the effects. However, all these molecules rescued the myotubes from Russell's viper venom-induced atrophy. This study demonstrates key steps in the muscle regeneration process that are affected by both Indian Russell's viper and cobra venoms and offers insights into the potential causes of clinical features displayed in envenomed victims. Further research is required to investigate the molecular mechanisms of venom-induced myotoxicity under in vivo settings and develop better therapies for snakebite-induced muscle damage., (© 2024. The Author(s).)

Bothrops and Lachesis are two of Brazil's medically most relevant snake genera, causing tens of thousands of bites annually. Fortunately, Brazil has good accessibility to high-quality antivenoms at the genus and inter-genus level, enabling the treatment of many of these envenomings. However, the optimal use of these treatments requires that the snake species responsible for the bite is determined. Currently, physicians use a syndromic approach to diagnose snakebite, which can be difficult for medical personnel with limited training in clinical snakebite management. In this work, we have developed a novel monoclonal antibody-based multiplex lateral flow assay for differentiating Bothrops and Lachesis venoms within 15 min. The test can be read by the naked eye or (semi)-quantitatively by a smartphone supported by a 3D-printed attachment for controlling lighting conditions. The LFA can detect Bothrops and Lachesis venoms in spiked plasma and urine matrices at concentrations spanning six orders of magnitude. The LFA has detection limits of 10-50 ng/mL in spiked plasma and urine, and 50-500 ng/mL in spiked sera, for B. atrox and L. muta venoms. This test could potentially support medical personnel in correctly diagnosing snakebite envenomings at the point-of-care in Brazil, which may help improve patient outcomes and save lives., (© 2024. The Author(s).)

Background: Currently, antivenoms are the only specific treatment available for snakebite envenoming. In Brazil, over 30% of patients cannot access antivenom within its critical care window. Researchers have therefore proposed decentralizing to community health centers to decrease time-to-care and improve morbidity and mortality. Currently, there is no evidence-based method to evaluate the capacity of health units for antivenom treatment, nor what the absolute minimum supplies and staff are necessary for safe and effective antivenom administration and clinical management., Methods: This study utilized a modified-Delphi approach to develop and validate a checklist to evaluate the minimum requirements for health units to adequately treat snakebite envenoming in the Amazon region of Brazil. The modified-Delphi approach consisted of four rounds: 1) iterative development of preliminary checklist by expert steering committee; 2) controlled feedback on preliminary checklist via expert judge survey; 3) two-phase nominal group technique with new expert judges to resolve pending items; and 4) checklist finalization and closing criteria by expert steering committee. The measure of agreement selected for this study was percent agreement defined a priori as ≥75%., Results: A valid, reliable, and feasible checklist was developed. The development process highlighted three key findings: (1) the definition of community health centers and its list of essential items by expert judges is consistent with the Brazilian Ministry of Health, WHO snakebite strategic plan, and a general snakebite capacity guideline in India (internal validity), (2) the list of essential items for antivenom administration and clinical management is feasible and aligns with the literature regarding clinical care (reliability), and (3) engagement of local experts is critical to developing and implementing an antivenom decentralization strategy (feasibility)., Conclusion: This study joins an international set of evidence advocating for decentralization, adding value in its definition of essential care items; identification of training needs across the care continuum; and demonstration of the validity, reliability, and feasibility provided by engaging local experts. Specific to Brazil, further added value comes in the potential use of the checklist for health unit accreditation as well as its applications to logistics and resource distribution. Future research priorities should apply this checklist to health units in the Amazon region of Brazil to determine which community health centers are or could be capable of receiving antivenom and translate this expert-driven checklist and approach to snakebite care in other settings or other diseases in low-resource settings., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Serrão-Pinto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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.

Snake envenoming is a major, but neglected, tropical disease. Among venomous snakes, those inducing neurotoxicity such as kraits (Bungarus genus) cause a potentially lethal peripheral neuroparalysis with respiratory deficit in a large number of people each year. In order to prevent the development of a deadly respiratory paralysis, hospitalization with pulmonary ventilation and use of antivenoms are the primary therapies currently employed. However, hospitals are frequently out of reach for envenomated patients and there is a general consensus that additional, non-expensive treatments, deliverable even long after the snake bite, are needed. Traumatic or toxic degenerations of peripheral motor neurons cause a neuroparalysis that activates a pro-regenerative intercellular signaling program taking place at the neuromuscular junction (NMJ). We recently reported that the intercellular signaling axis melatonin-melatonin receptor 1 (MT1) plays a major role in the recovery of function of the NMJs after degeneration of motor axon terminals caused by massive Ca2+ influx. Here we show that the small chemical MT1 agonists: Ramelteon and Agomelatine, already licensed for the treatment of insomnia and depression, respectively, are strong promoters of the neuroregeneration after paralysis induced by krait venoms in mice, which is also Ca2+ mediated. The venom from a Bungarus species representative of the large class of neurotoxic snakes (including taipans, coral snakes, some Alpine vipers in addition to other kraits) was chosen. The functional recovery of the NMJ was demonstrated using electrophysiological, imaging and lung ventilation detection methods. According to the present results, we propose that Ramelteon and Agomelatine should be tested in human patients bitten by neurotoxic snakes acting presynaptically to promote their recovery of health. Noticeably, these drugs are commercially available, safe, non-expensive, have a long bench life and can be administered long after a snakebite even in places far away from health facilities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 D’Este et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Morbidity from snakebite envenoming affects approximately 400,000 people annually. Tissue damage at the bite-site often leaves victims with catastrophic life-long injuries and is largely untreatable by current antivenoms. Repurposed small molecule drugs that inhibit specific snake venom toxins show considerable promise for tackling this neglected tropical disease. Using human skin cell assays as an initial model for snakebite-induced dermonecrosis, we show that the drugs 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat, and varespladib, alone or in combination, inhibit the cytotoxicity of a broad range of medically important snake venoms. Thereafter, using preclinical mouse models of dermonecrosis, we demonstrate that the dual therapeutic combinations of DMPS or marimastat with varespladib significantly inhibit the dermonecrotic activity of geographically distinct and medically important snake venoms, even when the drug combinations are delivered one hour after envenoming. These findings strongly support the future translation of repurposed drug combinations as broad-spectrum therapeutics for preventing morbidity caused by snakebite., (© 2023. The Author(s).)

Snakebite envenoming can be a life-threatening medical emergency that requires prompt medical intervention to neutralise the effects of venom toxins. Each year up to 138,000 people die from snakebites and threefold more victims suffer life-altering disabilities. The current treatment of snakebite relies solely on antivenom-polyclonal antibodies isolated from the plasma of hyperimmunised animals-which is associated with numerous deficiencies. The ADDovenom project seeks to deliver a novel snakebite therapy, through the use of an innovative protein-based scaffold as a next-generation antivenom. The ADDomer is a megadalton-sized, thermostable synthetic nanoparticle derived from the adenovirus penton base protein; it has 60 high-avidity binding sites to neutralise venom toxins. Here, we outline our experimental strategies to achieve this goal using state-of-the-art protein engineering, expression technology and mass spectrometry, as well as in vitro and in vivo venom neutralisation assays. We anticipate that the approaches described here will produce antivenom with unparalleled efficacy, safety and affordability.

Snakebite-related fatalities disproportionately affect populations in impoverished socio-economic regions, marked by limited access to adequate healthcare and constrained antivenom availability. Early medical intervention is pivotal in mitigating mortality and morbidity associated with snakebite envenoming (SBE). While clinical assessment remains fundamental in treating SBE, this review aims to spotlight objective parameters that could also affect outcomes. Selected studies that identify factors associated with poor outcomes are predominantly region-specific, single-site, and observational, yet collectively reveal similar findings. They consistently report factors such as treatment delays, susceptibility in vulnerable groups such as children and pregnant women, as well as various biochemical and haematological abnormalities. Acute kidney injury (AKI), low platelets, leucocytosis, abnormal coagulation, and elevated creatine kinase (CK) all show an association with poor outcomes. Furthermore, recognising rare and unusual SBE presentations such as adrenal insufficiency, severe hypertension, intracranial haemorrhage, acute angle closure glaucoma, and bowel ischaemia also has a bearing on outcomes. Despite the integration of these parameters into clinical decision tools and guidelines, the validation of this evidence is limited. This review underscores the imperative for high-quality, multi-centre studies aligned with consensus-driven Core Outcome Sets (COS) and Patient-Reported Outcome Measures (PROMS) to validate and strengthen the current evidence.

Background: Snakebites is a serious public health issue but remains a neglected tropical disease. Data on antivenom effectiveness are urgently needed in Africa. We assessed effectiveness of Inoserp PAN-AFRICA (IPA), the recommended antivenom available in Cameroon., Methodology/principal Findings: We enrolled 447 patients presenting with snakebite in 14 health facilities across Cameroon. At presentation, cytotoxicity, coagulation troubles and neurotoxicity were graded. We administered two to four vials of antivenom to patients based on hemotoxic or neurotoxic signs. We renewed antivenom administration to patients with persistence of bleedings or neurotoxicity 2 hours after each injection. We defined early improvement as a reduction of the grade of envenomation symptoms 2 hours after first injection. Medium-term effectiveness was investigated looking at disappearance of symptoms during hospitalization. After hospital discharge, a home visit was planned to assess long-term outcomes. Between October 2019 and May 2021, we enrolled 447 (93.7%), including 72% from the savannah regions. The median [IQR] age was 25 [14-40]. Envenomation was diagnosed in 369 (82.6%) participants. The antivenom was administered to 356 patients (96.5%) of whom 256 (71.9%) received one administration. Among these patients, cytotoxic symptoms were observed in 336 (94.4%) participants, coagulation disorders in 234 (65.7%) participants and neurotoxicity in 23 (6.5%) participants. Two hours after the first administration of antivenom, we observed a decrease in coagulation disorders or neurotoxicity in 75.2% and 39.1% of patients, respectively. Complete cessation of bleedings and neurotoxicity occurred in 96% and 93% of patients within 24 hours, respectively. Sequelae have been observed in 9 (3%) patients at the home visit 15 days after hospital admission and 11 (3%) died including one before antivenom injection., Conclusions/significance: We confirmed good effectiveness of the IPA and highlighted the rapid improvement in bleeding or neurotoxicity after the first administration. Sequential administrations of low doses of antivenom, rigorously assessed at short intervals for an eventual renewal, can preserve patient safety and save antivenom., Trial Registration: NCT03326492., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Chippaux et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Snakebite envenomation (SBE)-induced immunity refers to individuals who have been previously bitten by a snake and developed a protective immune response against subsequent envenomations. The notion stems from observations of individuals, including in the indigenous population, who present only mild signs and symptoms after surviving multiple SBEs. Indeed, these observations have engendered scientific interest and prompted inquiries into the potential development of a protective immunity from exposure to snake toxins. This review explores the evidence of a protective immune response developing following SBE. Studies suggest that natural exposure to snake toxins can trigger protection from the severity of SBEs, mediated by specific antibodies. However, the evaluation of the immune memory response in SBE patients remains challenging. Further research is needed to elucidate the immune response dynamics and identify potential targets for therapeutic interventions. Furthermore, the estimation of the effect of previous exposures on SBE epidemiology in hyperendemic areas, such as in the indigenous villages of the Amazon region (e.g., the Yanomami population) is a matter of debate.

Snakebite envenoming is a major global health problem that kills or disables half a million people in the world's poorest countries. Identifying the biting snake and its habitat use is key to understanding snakebite eco-epidemiology and optimizing its clinical management. To prevent and combat the neglected snakebite disease, we characterize the morphology, geographic distribution, habitat use, and snakebites of medically important venomous snakes in the state of Rio de Janeiro (Brazil). Despite Philodryas spp. not being considered of medical importance by the Brazilian Ministry of Health, we also explore their data once the bites may require medical intervention, may cause death, and their consequences are underestimated. Methods: We assessed taxonomy and geographic data from specimens housed in scientific collections, the literature, and the Notifiable Diseases Information System. Our data revealed fragility in the morphological characters recommended to distinguish Bothrops jararaca from B. jararacussu, identify the subspecies of Crotalus durissus and distinguish the species of Philodryas. To help identify these species, we present an identification key to the venomous snake species from Rio de Janeiro based on the morphological data collected. We record the genera Bothrops and Micrurus in all mesoregions of the state. Here, we provide the first record of C. durissus in the Serrana region, supporting the hypothesis of geographic expansion of the species in the state. The crotalic antivenom must not be missing in Médio Paraíba, Centro-Sul Fluminense, and Serrana, where the rattlesnake C. durissus occurs. Bothrops bilineatus and Lachesis muta have historical records presented for the first time herein. However, these species are likely endangered or extinct in the state. There were 7,483 snakebites reported between 2001 and 2019, with an annual average of 393.8 cases. The Bothrops genus is responsible for the majority of accidents. The highest number of cases occurred in the Serrana region, the largest pole of family agriculture in Rio de Janeiro. We improve the identification of venomous snake species, better delimit their distribution, and update the number of cases of snakebites, thus providing greater precision in the attention to this problem in Rio de Janeiro. We emphasize the importance of clinical studies to test using bothropic-crotalic antivenom and heparin in all mesoregions to treat B. jararacussu envenomation; and mechanical ventilation, atropine, and anticholinesterases in the emergency health centers in the Metropolitana and Norte Fluminense regions due to the occurrence of the coral M. lemniscatus in these areas.

Objective: To conduct a bibliometric analysis of the global snakebite literature to provide a reference for the future development of snakebite research. Methods: The Web of Science citation analysis tools, VOSviewer and CiteSpace V were used to carry out the bibliometric analysis of the literature and generate visualization maps. Results: The number of publications has increased at a considerably accelerated rate in the past 8 years. Nine distinct cooperation clusters were formed between institutions and countries. Keyword clustering yielded nine well-structured clusters covering two major topics, i.e., snakebite envenoming and antivenom. Burstiness detection revealed eight keywords with strong emergence, including neglected tropical diseases, Elapidae, Viperidae, and Russell's viper, which have sustained popularity up to the present. Conclusion: Current research on snakebites has gradually garnered attention from the academic community. Cooperation papers between nations severely affected by snakebite and those with higher economic status received more attention. The continued exploration of therapeutic mechanisms, the development of antivenoms or alternative medicines, and primary prevention of snakebites to ensure the safety of populations in impoverished regions should be prioritized by international scholars. The epidemiological evidence and the timely translation of research findings should be valued by policymakers., Competing Interests: The authors declare that they do not have any conflicts of interest., (Copyright © 2023 Lv, Lei, Hu, Song, Wang, Hao, He, Chen, Han, Gan and Yan.)

Background: India suffers ~58,000 annual deaths due to snakebites. The 'Big Four' snakes (Russell's viper, Indian cobra, common krait, and saw-scaled viper) that are responsible for most bites cause diverse clinical effects. Delayed treatment increases the risk of serious complications and treatment costs. Although government hospitals offer free treatment for snakebites in India, most patients opt for private healthcare, which is an out-of-pocket expense as they often lack health insurance coverage. This study aims to analyse snakebite treatment costs in private tertiary care hospitals in Tamil Nadu, India and identifies the key factors contributing to treatment costs., Methodology/principal Findings: The treatment cost details for 913 snakebite victims were collected from 10 private tertiary care hospitals across Tamil Nadu. The data were classified into hospital, pharmacy, investigation, and laboratory costs, and analysed to determine various factors that contribute to the costs. The results demonstrate that the average treatment costs vary widely for different snakes. The hospital and pharmacy costs are higher than investigation and laboratory costs for all snakebites. Notably, Russell's viper bites cost significantly more than the bites from other snakes. Overall, the type of snake, nature of complications, specialist treatments required, and arrival time to hospitals were identified as some of the key factors for higher treatment costs., Conclusions/significance: These data demonstrate that ~80% of snakebite patients can be treated with INR 100,000 (~GBP 1000 or USD 1200) or less. This study emphasises the urgent need to improve rural medical care by providing appropriate training for healthcare professionals and essential resources to facilitate early assessment of patients, administer the initial dose of antivenom and refer the patients to tertiary care only when needed. Moreover, the outcome of this study forms a basis for developing appropriate policies to regulate snakebite treatment costs and provide affordable medical insurance for vulnerable communities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Salim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Antivenom is currently the standard-of-care treatment for snakebite envenoming, but its efficacy is limited by treatment delays, availability, and in many cases, species specificity. Many of the rapidly lethal effects of envenoming are caused by venom-derived toxins, such as phospholipase A2 (sPLA2); therefore, small molecule direct toxin inhibitors targeting these toxins may have utility as initial and adjunct therapies after envenoming. Varespladib (intravenous, IV) and varespladib-methyl (oral) have been shown to potently inhibit sPLA2s from snake venoms in murine and porcine models, thus supporting their further study as potential treatments for snakebite envenoming. In this pilot study, we tested the ability of these compounds to reverse neurotoxic effects of venom from the Australian and Papuan taipan ( Oxyuranus scutellatus ) subspecies in juvenile pigs ( Sus domesticus ). The mean survival time for control animals receiving Australian taipan venom (0.03 mg/kg, n = 3) was 331 min ± 15 min; for those receiving Papuan taipan venom (0.15 mg/kg, n = 3) it was 178 ± 31 min. Thirteen pigs received Australian taipan venom and treatment with either IV or oral varespladib (or with IV to oral transition) and all 13 survived the duration of the study (≥96 h). Eight pigs received Papuan taipan venom followed by treatment: Briefly: Two animals received antivenom immediately and survived to the end of the study. Two animals received antivenom treatment delayed 45 min from envenoming and died within 4 h. Two animals received similarly delayed antivenom treatment and were rescued by varespladib. Two animals were treated with varespladib alone after a 45-min delay. Treatment with varespladib only was effective but required repeat dosing over the course of the study. Findings highlight both the importance of early treatment and, as well, a half-life for the investigational inhibitors now in Phase II clinical trials for snakebite. Varespladib rapidly reversed weakness even when administered many hours post-envenoming and, overall, our results suggest that varespladib and varespladib-methyl could be efficacious tools in the treatment of sPLA2-induced weakness from Oxyuranus envenoming. Further clinical study as initial therapy and as potential method of rescue from some types of antivenom-resistant envenomings are supported by these data.

Snake envenomation remains an important yet neglected medical problem in many countries, with around five million people affected, and over a hundred thousand deaths annually. Plasma-derived antivenoms are the main therapeutic agent available. Monovalent antivenoms are produced via the immunization of large animals, e.g., horses, with one venom, after which the horse serum can neutralize the homologous venom, with minimal or no cross neutralization against other venoms. It is necessary, therefore, for the culprit snake to be identified, so that the appropriate specific antivenom can be selected. Polyvalent antivenoms (pAVs) are produced via immunization with a number of snake venoms, and the serum can neutralize all the venoms used in its production. Thus, pAVs can be used to treat several venoms from a country/region, and the identification of the culprit snake is not necessary. There are various parameters and processes involved in the production of pAVs, depending on the requirements and resources available. Most commercial pAVs use a mixture of both elapid and viperid venoms as immunogens, while some pAVs use either elapid or viperid venoms. Some pAVs are produced through the mixing of more than one monovalent or polyvalent antivenom. These various types of pAVs have their own characteristics, and have benefits and drawbacks. The major benefits of pAVs are the wide coverage of many medically important venoms, including many heterologous venoms. They also remove the need to identify the culprit snake, and they can be produced at a lower cost than several monovalent antivenoms. Interesting polyvalent antivenoms, termed 'syndromic pAVs' (s-pAVs), have recently gained attention. They are produced for use according to the syndromes manifested in snakebite patients. The venoms that produce these syndromes are used as immunogens in the production of 'syndromic antivenoms'. For example, 'neurotoxic polyvalent antivenom' and 'hematotoxic polyvalent antivenom' are produced using the neurotoxic elapid and hematotoxic viperid venoms as immunogens, respectively. They were first marketed by the Thai Red Cross in 2012, and have since gained attention as a possible therapeutic modality to help solve the problem of snakebite envenomation globally. The merits of these s-pAVs, including their efficacy and wide paraspecificities, are discussed.

The limitations posed by currently available antivenoms have emphasized the need for alternative treatments to counteract snakebite envenomation. Even though exact epidemiological data are lacking, reports have indicated that most global snakebite deaths are reported in India. Among the many problems associated with snakebite envenomation, issues related to the availability of safer and more efficient antivenoms are of primary concern. Since India has the highest number of global snakebite deaths, efforts should be made to reduce the burden associated with snakebite envenoming. Alternative methods, including aptamers, camel antivenoms, phage display techniques for generating high-affinity antibodies and antibody fragments, small-molecule inhibitors, and natural products, are currently being investigated for their effectiveness. These alternative methods have shown promise in vitro, but their in vivo effectiveness should also be evaluated. In this review, the issues associated with Indian polyvalent antivenoms in neutralizing venom components from geographically distant species are discussed in detail. In a nutshell, this review gives an overview of the current drawbacks of using animal-derived antivenoms and several alternative strategies that are currently being widely explored.

This study investigated the clinical characteristics, treatments, and outcomes of envenomation involving cobra species in Thailand ( Naja kaouthia , Naja siamensis , and Naja sumatrana ). Data of patients who had been bitten by a cobra or inoculated via the eyes/skin in 2018-2021 were obtained from the Ramathibodi Poison Center. There were 1045 patients admitted during the 4-year study period (bite, n = 539; ocular/dermal inoculation, n = 506). Almost all patients with ocular/dermal inoculation had eye involvement and ocular injuries, but none had neurological effects. Most of the patients bitten by a cobra had local effects (69.0%) and neurological signs and symptoms (55.7%). The median interval between the bite and the onset of neurological symptoms was 1 h (range, 10 min to 24 h). Accordingly, patients should be observed closely in hospitals for at least 24 h after a bite. Intubation with ventilator support was required in 45.5% of patients and for a median duration of 1.1 days. Antivenom was administered in 63.5% of cases. There were nine deaths, most of which resulted from severe infection. Neurological effects and intubation were significantly more common after a monocled cobra bite than after a spitting cobra bite. The administration of antivenom with good supportive care, including the appropriate management of complications, especially wound infection, might decrease fatality.

Background: Cross-neutralizing strategy has been applied to improve access to antivenoms, a key to reducing mortality and disability of snakebite envenoming. However, preclinical studies have been conducted to identify antivenoms' cross-neutralizing ability when clinical studies may not be considered ethical. Therefore, this study aimed to identify and summarize scattered evidence regarding the preclinical efficacy of antivenoms against Asian snakes., Methodology/principle Findings: In this systematic review, we searched for articles published until May 30, 2022, in PubMed, Scopus, Web of Science, and Embase. Preclinical studies that reported the available antivenoms' neutralizing ability against Asian snake lethality were included. Quality assessment was performed using the Systematic Review Centre for Laboratory animal Experimentation's risk of bias tool and the adapted the Animal Research Reporting In Vivo Experiments guidelines. The availability of effective antivenoms against Asian snakes was analyzed by comparing data from included studies with snakebite-information and data platforms developed by the World Health Organization. Fifty-two studies were included. Most studies assessed the antivenom efficacy against snakes from Southeast Asia (58%), followed by South Asia (35%) and East Asia (19%). Twenty-two (49%) medically important snakes had antivenom(s) with confirmed neutralizing ability. Situation analyses of the availability of effective antivenoms in Asia demonstrated that locally produced antivenoms did not cover all medically important snakes in each country. Among countries without local antivenom production, preclinical studies were conducted only in Bangladesh, Sri Lanka, and Malaysia. Risk of bias assessment was limited in some domains because of unreported data., Conclusions/significance: Cross-neutralizing of antivenoms against some medically important snakes in Asia was confirmed. This strategy may improve access to geographically effective antivenoms and bypass investment in novel antivenom development, especially in countries without local antivenom production. A database should be developed to aid the development of a snakebite-information system., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Soopairin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: In 2018, Anavip became available for the treatment of rattlesnake envenomations in the USA. No comparisons between the treatment characteristics of patients have been made since Anavip and CroFab have both been widely available. The objective of this study was to compare the number of antivenom vials administered of CroFab and Anavip during the treatment of rattlesnake envenomations in the USA., Methods: This was a secondary analysis of rattlesnake envenomations utilizing the North American Snakebite Registry (NASBR) from 2019 through 2021. Frequencies and proportions were used to summarize demographics and baseline clinical characteristics. The primary outcome was total antivenom vials administered during treatment. Secondary outcomes included the number antivenom administration events, total treatment time, and hospital length of stay., Results: Two hundred ninety-one rattlesnake envenomations were analyzed; most occurred in the Western USA (n = 279, 96 %). One hundred one patients (35%) received only CroFab, 110 (38%) received Anavip only, and 80 (27%) received both products. The median number of vials used was 10 for CroFab, 18 for Anavip, and 20 for both antivenoms. More than one antivenom administration was necessary in thirty-nine (39%) patients that received only CroFab and 76 (69%) patients that received Anavip only. The median total treatment time was 5.5 hours for CroFab, 6.5 for Anavip, and 15.5 hours when both antivenoms were administered. All antivenom groups had a median hospital length of stay of 2 days., Conclusions: Rattlesnake envenomated patients in the Western USA treated with CroFab had fewer antivenom vials and fewer antivenom administrations compared to patients treated with Anavip., (© 2023. The Author(s).)

Envenomations induced by animal bites and stings constitute a significant public health burden. Even though a standardized protocol does not exist, parenterally administered polyclonal antivenoms remain the mainstay in snakebite therapy. There is a prevailing opinion that their application by the i.m. route has poor efficacy and that i.v. administration should preferentially be chosen in order to achieve better accomplishment of the antivenom therapeutic activity. Recently, it has been demonstrated that neutralization not only in the systemic circulation but also in the lymphatic system might be of great importance for the clinical outcome since it represents another relevant body compartment through which the absorption of the venom components occurs. In this review, the present-day and summarized knowledge of the laboratory and clinical findings on the i.v. and i.m. routes of antivenom administration is provided, with a special emphasis on the contribution of the lymphatic system to the process of venom elimination. Until now, antivenom-mediated neutralization has not yet been discussed in the context of the synergistic action of both blood and lymph. A current viewpoint might help to improve the comprehension of the venom/antivenom pharmacokinetics and the optimal approach for drug application. There is a great need for additional dependable, practical, well-designed studies, as well as more practice-related experience reports. As a result, opportunities for resolving long-standing disputes over choosing one therapeutic principle over another might be created, improving the safety and effectiveness of snakebite management.