Important Snake Research Articles

Epidemiological patterns and trends of paediatric snakebites in Sri Lanka

ObjectivesThis study aimed to analyse the epidemiological patterns of paediatric snake bites in Sri Lanka over a 4-year period (2020–2024).MethodsA multi-centre, retrospective observational study was conducted from June 2020 to June 2024 across nine governmental hospitals in seven provinces of Sri Lanka. Data were collected based on 757 children presenting with snake bites. The snake bites were analysed based on age, gender, and seasonal variations. Data on the type of snake involved, geographic variations and the temporal trends in snake bite occurrences were also analysed.ResultsThe mean age of the 757 children recruited to the study was 10.3 years (SD—5.00, range—0.1–17 years). Males (57.7%) were significantly more affected than females (42.3%) (p < 0.05). Visual identification confirmed the snake species in 58.4% of cases. The hump-nosed viper (16.7%), Russell’s viper (14.7%), and common krait (12.9%) were the most common medically important snakes identified in the study. Seasonal peaks in snake bites occurred in May–July and November–December. An increasing trend in snake bite incidence was noted over the first three years, with a slight decline in the final year.ConclusionPaediatric snake bites in Sri Lanka show significant age, gender, and seasonal patterns. Targeted public health interventions are needed to mitigate the impact on children.

Analysis of Naja kaouthia snake venom composition and in-vitro enzymatic activities of 29 specimens in captivity: Highlighting the importance of individual variation in venom pool production

Naja kaouthia is a medically important snake, widely distributed throughout Southeast Asia, with a diverse venom composition. N. kaouthia venom is subject to significant intraspecific variation, caused by several factors, such as the wide geographic distribution of the species, sexual and ontogenetic factors. However, individual variation is a factor that has only been studied with small sample size groups and/or with pooled samples. With this in mind, this study evaluates the composition and in-vitro enzymatic activities of 29 individual venom samples from specimens born in captivity, with a similar genetic background caused by inbreeding, using SDS-PAGE under reducing conditions, RP-HPLC profiles and enzymatic activities of PLA2, LAAO and proteolytic activity over azocasein. Even in this scenario, we were able to observe significant variations in abundance and activity of PLA2. Individual variations in LAAO activity, as well as a sexual dimorphism in which males present a significantly higher LAAO activity than females were observed. Phosphodiasterase and CRiSP abundance were also found and considered to have multiple effects in the clinical manifestations of envenomation by presenting synergistic effects with other proteins from N. kaouthia venom. The RP-HPLC profiles were better at detecting compositional differences than SDS-PAGE profiles and better correlated with enzymatic activities, being a better technique to screen variation profiles and reinforcing the importance of individual venom analysis prior to pooling.

Ontogeny, not prey availability, underlies allopatric venom variability in insular and mainland populations of Vipera ammodytes

Allopatric populations living under distinct ecological conditions are excellent systems to infer factors underlying intraspecific venom variation. The venom composition of two populations of Vipera ammodytes, insular with a diet based on ectotherms and mainland with a diet based on ectotherms and endotherms, was compared considering the sex and age of individuals. Ten toxin families, dominated by PLA2, svMP, svSP, and DI, were identified through a bottom-up approach. The venom profiles of adult females and males were similar. Results from 58 individual SDS-PAGE profiles and venom pool analysis revealed significant differences between juveniles compared to subadults and adults. Two venom phenotypes were identified: a juvenile svMP-dominated and KUN-lacking phenotype and an adult PLA2/svMP-balanced and KUN-containing phenotype. Despite differences in prey availability (and, therefore, diet) between populations, no significant differences in venom composition were found. As the populations are geographically isolated, the lack of venom diversification could be explained by insufficient time for natural selection and/or genetic drift to act on the venom composition of island vipers. However, substantial differences in proteomes were observed when compared to venoms from geographically distant populations inhabiting different conditions. These findings highlight the need to consider ecological and evolutionary processes when studying venom variability. SignificanceThis study provides the first comprehensive analysis of the venom composition of two allopatric populations of Vipera ammodytes, living under similar abiotic (climate) but distinct biotic (prey availability) conditions. The ontogenetic changes in venom composition, coupled with the lack of differences between sex and between populations, shed light on the main determinants of venom evolution in this medically important snake. Seven new proteomes may facilitate future comparative studies of snake venom evolution. This study highlights the importance of considering ecological and evolutionary factors to understand snake venom variation.

Fibrinogenolytic potential of venoms of medically important Brazilian snakes

One of the main clinical manifestations presented by victims of snake bite envenoming are coagulation disorders. Considering that fibrinogen is a key molecule for crosslinked fibrin clot formation, the objective of this work was the quantitative analysis of the fibrinogenolytic activity of snakes of medical importance in Brazil and neutralization by specific antivenom. For this, pools of three genera of medical importance (Bothrops, Crotalus and Lachesis) that are used for the production of antivenom were used, and three pools of species of the genus Bothrops that are not part of the pool for the production of antivenom. The Lachesis pool had the highest fibrinogenolytic activity, even demonstrating partial cleavage (42.9 % consumption) of the fibrinogen gamma chain. The Bothrops genus venom pools have shown subtle variations between them. The Crotalus pool, despite not showing total cleavage of any fibrinogen chain, began cleavage of fibrinogen by the beta chain. The specific antivenoms used were able to delay the cleavage of fibrinogen in all the venoms used, which could be the first step towards implementing previous in vitro tests to analyze the quality of the batches of antivenoms produced, thus potentially reducing the use of animals used in this process.

Nanofractionation Analytics for Comparing MALDI-MS and ESI-MS Data of Viperidae Snake Venom Toxins.

Worldwide, it is estimated that there are 1.8 to 2.7 million cases of envenoming caused by snakebites. Snake venom is a complex mixture of protein toxins, lipids, small molecules, and salts, with the proteins typically responsible for causing pathology in snakebite victims. For their chemical characterization and identification, analytical methods are required. Reversed-phase liquid chromatography coupled with electrospray ionization mass spectrometry (RP-LC-ESI-MS) is a widely used technique due to its ease of use, sensitivity, and ability to be directly coupled after LC separation. This method allows for the efficient separation of complex mixtures and sensitive detection of analytes. On the other hand, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is also sometimes used, and though it typically requires additional sample preparation steps, it offers desirable suitability for the analysis of larger biomolecules. In this study, seven medically important viperid snake venoms were separated into their respective venom toxins and measured by ESI-MS. In parallel, using nanofractionation analytics, post-column high-resolution fractionation was used to collect the eluting toxins for further processing for MALDI-MS analysis. Our comparative results showed that the deconvoluted snake venom toxin masses were observed with good sensitivity from both ESI-MS and MALDI-MS approaches and presented overlap in the toxin masses recovered (between 25% and 57%, depending on the venom analyzed). The mass range of the toxins detected in high abundance was between 4 and 28 kDa. In total, 39 masses were found in both the ESI-MS and/or MALDI-MS analyses, with most being between 5 and 9 kDa (46%), 13 and 15 kDa (38%), and 24 and 28 kDa (13%) in size. Next to the post-column MS analyses, additional coagulation bioassaying was performed to demonstrate the parallel post-column assessment of venom activity in the workflow. Most nanofractionated venoms exhibited anticoagulant activity, with three venoms additionally exhibiting toxins with clear procoagulant activity (Bothrops asper, Crotalus atrox, and Daboia russelii) observed post-column. The results of this study highlight the complementarity of ESI-MS and MALDI-MS approaches for characterizing snake venom toxins and provide a complementary overview of defined toxin masses found in a diversity of viper snake venoms.

From birth to bite: the evolutionary ecology of India's medically most important snake venoms

BackgroundSnake venoms can exhibit remarkable inter- and intraspecific variation. While diverse ecological and environmental factors are theorised to explain this variation, only a handful of studies have attempted to unravel their precise roles. This knowledge gap not only impedes our understanding of venom evolution but may also have dire consequences on snakebite treatment. To address this shortcoming, we investigated the evolutionary ecology of venoms of Russell’s viper (Daboia russelii) and spectacled cobra (Naja naja), India’s two clinically most important snakes responsible for an alarming number of human deaths and disabilities.MethodologySeveral individuals (n = 226) of D. russelii and N. naja belonging to multiple clutches (n = 9) and their mothers were maintained in captivity to source ontogenetic stage-specific venoms. Using various in vitro and in vivo assays, we assessed the significance of prey, ontogeny and sex in driving venom composition, function, and potency.ResultsConsiderable ontogenetic shifts in venom profiles were observed in D. russelii, with the venoms of newborns being many times as potent as juveniles and adults against mammalian (2.3–2.5 ×) and reptilian (2–10 ×) prey. This is the first documentation of the ontogenetic shift in viperine snakes. In stark contrast, N. naja, which shares a biogeographic distribution similar to D. russelii, deployed identical biochemical cocktails across development. Furthermore, the binding kinetics of cobra venom toxins against synthetic target receptors from various prey and predators shed light on the evolutionary arms race.ConclusionsOur findings, therefore, provide fascinating insights into the roles of ecology and life history traits in shaping snake venoms.

A Nationwide Study on the Risks of Complications and Healthcare Costs of Snakebite Envenomation in Taiwan.

In Taiwan, six medically important venomous snakes, Trimeresurus stejnegeri stejnegeri, Protobothrops mucrosquamatus, Deinagkistrodon acutus, Daboia siamensis, Naja atra, and Bungarus multicinctus, are found. However, comprehensive research on the complications and associated healthcare costs of snakebite envenomation (SBE) is lacking. We retrospectively analyzed pertinent information from the Taiwan National Health Insurance Research Database dated January 2002 to December 2014. We investigated the risk factors for complications and their impact on healthcare costs. Among the 12,542 patients with SBE, those from N. atra or B. multicinctus were more likely to experience wound infections and neurological complications than were those from T. s. stejnegeri or P. mucrosquamatus. In addition, being female, being elderly, and having a Charlson Comorbidity Index equal to or greater than 3 points were associated with an increased likelihood of wound infections and psychological complications. The annual national economic burden averaged US$1,083,624, with an average healthcare cost of US$1,129 per SBE. Snakebite envenomations from N. atra or B. multicinctus, as well as various complications, resulted in significantly higher costs. It is crucial to comprehend the risk factors for complications and their role in increasing expenses to provide insight for tailored healthcare interventions, mitigate complications, and reduce the economic burdens associated with SBEs.

CTXP, The Major Cobra Toxin Peptide from Naja Naja Oxiana Venom; A Promising Target for Antivenom Agent Development.

Snakebite envenoming is a serious public health issue causing more than 135,000 annual deaths worldwide. Naja Naja Oxiana is one of the most clinically important venomous snakes in Iran and Central Asia. Conventional animal-derived polyclonal antibodies are the major treatment of snakebite envenoming. Characterization of venom components helps to pinpoint the toxic protein responsible for clinical manifestations in victims, which aids us in developing efficient antivenoms with minimal side effects. Therefore, the present study aimed to identify the major lethal protein of Naja Naja Oxiana by top-down proteomics. Venom proteomic profiling was performed using gel filtration (GF), reversed-phase (RP) chromatography, and intact mass spectrometry. The toxicity of GF-, and RP-eluted fractions was analyzed in BALB/c mice. The rabbit polyclonal antisera were produced against crude venom, GF fraction V (FV), and RP peak 1 (CTXP) and applied in neutralization assays. Toxicity studies in BALB/c identified FV as the major toxic fraction of venom. Subsequently, RP separation of FV resulted in eight peaks, of which peak 1, referred to as "CTXP" (cobra toxin peptide), was identified as the major lethal protein. In vivo neutralization assays using rabbit antisera showed that polyclonal antibodies raised against FV and CTXP are capable of neutralizing at least 2-LD50s of crude venom, FV, and CTXP in all tested mice. Surprisingly, the Anti-CTXP antibody could neutralize 8-LD50 of the CTXP peptide. These results identified CTXP (a 7 kDa peptide) as a potential target for the development of novel efficient antivenom agents.

First record of two species of venomous snakes Bungarus suzhenae and Ovophis zayuensis (Serpentes: Elapidae, Viperidae) from India

We report Bungarus suzhenae Chen, Shi, Vogel, Ding &amp; Shi, 2021 and Ovophis zayuensis (Jiang, 1977) for the first time from India. Specimens of B. suzhenae and O. zayuensis were collected during our field surveys in north (Arunachal Pradesh) and south (Nagaland-Manipur border) of the river Brahmaputra. Species identity was supported by partial cytochrome b (cyt b), and 16s mitochondrial gene. We provide a detailed morphological description and a key to the two genera of this region. This report extends the westernmost distribution of B. suzhenae by ca. 300 km from Myanmar, and the southernmost range of O. zayuensis by 170 km from Tibet. Until now eight species of Bungarus and only one Ovophis species have been reported from India. Ovophis species are recently reported to be medically important venomous snakes whose venom properties have not been investigated in depth.

Harnessing the Cross-Neutralisation Potential of Existing Antivenoms for Mitigating the Outcomes of Snakebite in Sub-Saharan Africa.

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.

Epidemiological and sociodemographic description of snakebite envenoming cases in Paraguay reported between 2015 and 2021

IntroductionSnakebite envenoming (SBE) is a public health problem in Paraguay where the presence of 15 medically important snake species has been reported. Blessed with large forested areas, its economy largely...

Ruthenium-based antivenom attenuates Crotalus atrox venom mediated coagulopathy in rabbits.

The Western diamondback rattlesnake ( Crotalus atrox ) is a medically important venomous snake in the Southwestern United States, injuring humans, and their companion animals. The goals of this investigation were to utilize a rabbit model of subcutaneous envenomation to assess Crotalus atrox venom coagulopathy and determine the efficacy of a ruthenium-containing antivenom (RA) in attenuating it. Sedated New Zealand White rabbits had viscoelastic measurements of whole blood coagulation kinetics obtained from ear artery samples. Crotalus atrox venom (4 mg/kg) was injected subcutaneously and changes in coagulation determined over three hours and compared to samples obtained prior to envenomation. Other rabbits had site-directed RA injected 5 min after venom injection. A significant decrease in the velocity of clot growth and thrombus strength was observed in animals injected with venom alone. Site-directed administration of RA resulted in no change in coagulation over the 3 h following venom injection. The interaction of antivenom administration and time was significantly different in the cases of clot growth velocity and strength. A novel rabbit model was used to define the toxicodynamic profile of coagulopathy of Crotalus atrox venom and demonstrate the efficacy of RA. Future investigation is planned involving other medically important venoms and RA administration.

Differential effects of the venoms of Russell’s viper and Indian cobra on human myoblasts

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 A2 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.

Proteomic Analysis and Immunoprofiling of Persian Horned Viper Venom, Pseudocerastes Persicus, from Central Part of Iran.

Numerous species of venomous snakes of medical importance exist in Iran. Pseudocerastes persicus (P. persicus), one of the medically important snakes, also called the Persian horned viper, has a geographical spread that extends to the east, southwest, and central areas of Iran and is endemic across the wider region. As a result, this species is responsible for many snakebite occurrences. Venom from P. persicus found in the central province of Semnan contains phospholipase A2 and L-amino acid oxidase activities, and high toxic potency. The venom was fractionated by reverse-phase high-performance liquid chromatography (HPLC) and analyzed by Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), Western blotting and two-dimensional electrophoresis. Using liquid chromatography with tandem mass spectrometry (LC-MS/MS), a range of components were identified, consistent with the biochemical and toxicological properties of the venom. Proteins identified from 2D electrophoresis and shotgun methods included metallo- and serine proteases, phospholipases, oxidases, and Kunitz trypsin inhibitors, along with many other components at lower qualitative abundance. This study provides a more detailed understanding of the protein profile of Iranian P. persicus venom, which can be effective in the production of an effective antidote against it. The analysis of the resulting data shows that there is a wide range of proteins in the venom of the Persian horned viper. This information can provide a better understanding of how venom is neutralized by polyclonal antivenom. Considering the wide presence of this snake and its related species in Iran and surrounding countries, knowing the venom protein profile of this family can be of great support to antivenom producers such as Razi Vaccine & Serum Research Institute in the preparation of regional antivenoms.

Clinical Laboratory Investigations and Antivenom Administration after Malayan Pit Viper (Calloselasma rhodostoma) Envenoming: A Retrospective Study from Southernmost Thailand.

The Malayan pit viper (MPV: Calloselasma rhodostoma) is a medically important venomous snake causing numerous envenomations in Thailand. Administration of specific snake antivenom is the only effective treatment for MPV-envenomed patients. However, inappropriate administration or misuse of snake antivenom is problematic in some remote areas of tropical countries where the snakebite envenoming rate is notable. Currently, the indications for administration of MPV antivenom are focused mainly on hematological factors. These include 1) venous clotting time > 20 min, 2) unclotted 20-minute whole-blood clotting time, 3) international normalized ratio > 1.2, 4) platelet count < 50 × 103/μL, 5) systemic bleeding, and 6) impending compartment syndrome. We aimed to determine the association between laboratory data and antivenom administration in MPV-envenomed patients. A retrospective study of data from 2016 to 2021 in Narathiwat Province, the southernmost province in Thailand, was conducted. A total of 838 MPV-bitten patients were included in this study. Local effects and systemic effects were observed in 58.8% and 27.7% of patients, respectively. Coagulopathies, which range from abnormal blood clotting to systemic bleeding, represented the majority of systemic effects. Acute kidney injury developed in 2.5% of patients. In this study, 57.3% of patients were considered appropriate antivenom recipients. Interestingly, the present study revealed that local bleeding and mild to moderate thrombocytopenia became the independent factors for inappropriate use of MPV antivenom. Reeducation and supervision regarding the rational use of snake antivenom are needed to minimize the misuse of antivenom.

Toxicological analyses of the venoms of Nigerian vipers Echis ocellatus and Bitis arietans

BackgroundAmong the medically important snakes in Nigeria, Echis ocellatus and Bitis arietans have the most lethal venom. These venoms were classified according to the presence of snake venom metalloproteinases (SVMPs), snake venom phospholipase A2 (PLA2s), and snake venom serine proteases (SVSPs). Toxicological analyzes were performed to understand the significance of different protein families in venoms.MethodsProteins were separated from venom using column chromatography. The skin and footpad of mice were used to determine hemorrhagic and edematogenic activities. Caprine blood plasma was used to test fibrinolytic activity in vitro.ResultsThe results showed that, compared to the crude venom, the SVMP fraction induced hemorrhagic effects with a diameter of 26.00 ± 1.00 mm in E. ocellatus and 21.33 ± 1.52 mm in B. arietans. Both SVSP and SVMP had anticoagulant effects; however, the SVSP fraction had a stronger effect, with a longer anticoagulation time of 30.00 ± 3.00 min in E. ocellatus and 26.00 ± 2.00 min in B. arietans. These main venom toxins, SVMPs, SVSPs, and PLA2, were found to have edema-forming effects that were optimal at 2 h after envenomation. PLA2s had the highest edema-inducing activity, with onset 30 min after envenomation.ConclusionsGiven the importance of SVMPs in altering the integrity of the membrane structure and impairing the blood coagulation system, an antivenom that can specifically neutralize its activity could inhibit the hemorrhage effects of the venoms.

Optimizing drug discovery for snakebite envenoming via a high-throughput phospholipase A2 screening platform.

Snakebite envenoming is a neglected tropical disease that causes as many as 1.8 million envenomings and 140,000 deaths annually. To address treatment limitations that exist with current antivenoms, the search for small molecule drug-based inhibitors that can be administered as early interventions has recently gained traction. Snake venoms are complex mixtures of proteins, peptides and small molecules and their composition varies substantially between and within snake species. The phospholipases A2 (PLA2) are one of the main pathogenic toxin classes found in medically important viper and elapid snake venoms, yet varespladib, a drug originally developed for the treatment of acute coronary syndrome, remains the only PLA2 inhibitor shown to effectively neutralise venom toxicity in vitro and in vivo, resulting in an extremely limited drug portfolio. Here, we describe a high-throughput drug screen to identify novel PLA2 inhibitors for repurposing as snakebite treatments. We present method optimisation of a 384-well plate, colorimetric, high-throughput screening assay that allowed for a throughput of ∼2,800 drugs per day, and report on the screening of a ∼3,500 post-phase I repurposed drug library against the venom of the Russell's viper, Daboia russelii. We further explore the broad-spectrum inhibitory potential and efficacy of the resulting top hits against a range of medically important snake venoms and demonstrate the utility of our method in determining drug EC50s. Collectively, our findings support the future application of this method to fully explore the chemical space to discover novel PLA2-inhibiting drugs of value for preventing severe pathology caused by snakebite envenoming.

Elusive elapids: biogeographic venom variation in Indian kraits and its repercussion on snakebite therapy.

Snakebite is a major public health concern in many parts of the world, including India, where over 58,000 deaths occur annually due to snake envenoming. The common krait (Bungarus caeruleus) is responsible for the second-highest number of snakebite-related mortalities in the country. However, despite its notoriety, little is known about its venom ecology, functions and compositional variation across bioclimatic zones, partly because these nocturnal snakes are highly elusive, making it difficult to find them in the wild. We aim to address this knowledge gap by characterising the venom composition and toxicity profiles of the pan-Indian populations (n = 8) of B. caeruleus using a combination of proteomics, receptor-toxin interaction assays, biochemical experiments, pharmacological tests and preclinical evaluations. We reveal considerable variation in venom composition, functions, and pharmacological activities among the geographically distinct populations of B. caeruleus. Furthermore, toxin-receptor interaction assays provide insights into their feeding ecology and prey-predator interactions. Finally, in vitro and in vivo experiments revealed the poor neutralising potencies of Indian antivenoms towards most populations of the common krait. Our findings highlight the alarming need to develop efficacious snakebite therapy in India to treat bites from this medically most important elapid snake.

Systematic review and meta-analysis on the efficacy of Indian polyvalent antivenom against the Indian snakes of clinical significance.

Snakebite in India is a severe problem as it causes a mortality rate of 58,000 and a disability rate of 140,000 every year which is the highest among any other country. Antivenom is the primary therapy for snakebite, and its manufacturing techniques have essentially stayed unaltered for over a century. Indian polyvalent antivenom, a scientifically validated medicine for treating the toxic effects of snakebites, is available against the venom of the so-called Big Four snakes namely Spectacled cobra (Naja naja), Saw-scaled viper (Echis carinatus), Russell's viper (Daboia russelli) and the Common krait (Bungarus caeruleus), responsible for majority of the deaths in India. India hosts many other species of snakes, including cobras, kraits, saw-scaled vipers, sea snakes, and pit vipers, responsible for clinically severe envenomation. Neutralization strategy has been applied to access the efficacy of antivenoms, crucial for reducing snake bite deaths and disabilities. This review aims to conduct a systematic review and meta-analysis on the neutralization efficiency of the Polyvalent Antivenom (PAV) and focus on the factors that may contribute to the poor recognition of the antivenom towards the venom toxins. Reports focusing on the investigation of antivenom efficacy were searched and collected from several databases. Preclinical studies that reported the neutralization efficacy of the commercial antivenom against the medically important snakes of India were included. The articles were screened based on the inclusion criteria and 8 studies were shortlisted for meta-analysis. Pooled proportion was calculated for the antivenom efficacy reported by the studies and was found to be statistically significant with a 95% confidence interval. The heterogenicity in the venom toxicity and neutralization potency of the antivenom was evident in the overall estimate (proportion) and individual data. We provide comprehensive evidence on antivenom efficacy against medically important snakes from various parts of India which may aid in identifying the gaps in snake envenomation therapy and the need for novel potentially improved treatment of snakebites.

Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

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.