Venom diversity in Naja mossambica: Insights from proteomic and immunochemical analyses reveal intraspecific differences.

BACKGROUND: Intraspecific variations in snake venom composition have been extensively documented, contributing to the diverse clinical effects observed in envenomed patients. Understanding these variations is essential for developing effective snakebite management strategies and targeted antivenom therapies. We aimed to comprehensively investigate venoms from three distinct populations of N. mossambica from Eswatini, Limpopo, and KwaZulu-Natal regions in Africa in terms of their protein composition and reactivity with three commercial antivenoms (SAIMR polyvalent, EchiTAb+ICP, and Antivipmyn Africa). METHODOLOGY/PRINCIPAL FINDINGS: Naja mossambica venoms from Eswatini region exhibited the highest content of neurotoxic proteins, constituting 20.70% of all venom proteins, compared to Limpopo (13.91%) and KwaZulu-Natal (12.80%), and was characterized by the highest diversity of neurotoxic proteins, including neurotoxic 3FTxs, Kunitz-type inhibitors, vespryns, and mamba intestinal toxin 1. KwaZulu-Natal population exhibited considerably lower cytotoxic 3FTx, higher PLA2 content, and significant diversity in low-abundant proteins. Conversely, Limpopo venoms demonstrated the least diversity as demonstrated by electrophoretic and mass spectrometry analyses. Immunochemical assessments unveiled differences in venom-antivenom reactivity, particularly concerning low-abundance proteins. EchiTAb+ICP antivenom demonstrated superior reactivity in serial dilution ELISA assays compared to SAIMR polyvalent. CONCLUSIONS/SIGNIFICANCE: Our findings reveal a substantial presence of neurotoxic proteins in N. mossambica venoms, challenging previous understandings of their composition. Additionally, the detection of numerous peptides aligning to uncharacterized proteins or proteins with unknown functions underscores a critical issue with existing venom protein databases, emphasizing the substantial gaps in our knowledge of snake venom protein components. This underscores the need for enhanced research in this domain. Moreover, our in vitro immunological assays suggest EchiTAb+ICP's potential as an alternative to SAIMR antivenom, requiring confirmation through prospective in vivo neutralization studies.

Analysis of intra-specific variations in the venom of individual snakes based on Raman spectroscopy.

The knowledge of variations in the composition of venoms from different snakes is important from both theoretical and practical points of view, in particular, at developing and selecting an antivenom. Many studies on this topic are conducted with pooled venoms, while the existence and significance of variations in the composition of venoms between individual snakes of the same species are emphasized by many authors. It is important to study both inter- and intra-specific, including intra-population, venom variations, because intra-specific variations in the venom composition may affect the effectiveness of antivenoms as strongly as inter-specific. In this work, based on venom Raman spectroscopy with principal component analysis, we assessed the variations in venoms of individual snakes of the Vipera nikolskii species from two populations and compared these intra-specific variations with inter-specific variations (with regard to the other related species). We demonstrated intra-specific (inter- and intra-population) differences in venom compositions which are smaller than inter-specific variations. We also assessed the compositions of V. nikolskii venoms from two populations to explain inter-population differences. The method used is rapid and requires virtually no preparation of samples, used in extremely small quantities, allowing the venoms of individual snakes to be analyzed. In addition, the method is informative and capable of detecting fairly subtle differences in the composition of venoms.

Acute compartment syndrome and fasciotomy after a viper bite in Italy: a case report.

BACKGROUND: Bites caused by European vipers are rare medical emergencies but can occasionally cause life-threatening complications. Viper venom causes local symptoms, which can be accompanied by systemic manifestations in severe cases. The local effects of snakebites include edema and, more rarely, necrosis and compartment syndrome. The consequences of envenomation are often more pronounced in children due to their smaller body size. CASE PRESENTATION: We present the case of a 6-year-old girl who experienced multiple viper bites in the lower limb in northwest Italy. The girl received supportive care but progressed to develop compartment syndrome that required emergency fasciotomy. The patient's condition improved promptly after surgical decompression and administration of antivenom, but full recovery required prolonged hospitalization and rehabilitation. CONCLUSIONS: This case highlights the importance of obtaining a timely assessment of the severity of viper envenomation without delaying the administration of antivenom in most serious cases. The presence of multiple bite marks on the patient is one factor that may help to predict the clinical severity of snakebites and anticipate symptom progression.

Snakebite envenoming: A systematic review and meta-analysis of global morbidity and mortality.

BACKGROUND: Snakebite envenoming represents a significant and often neglected public health challenge, particularly in rural communities across tropical and subtropical regions. An estimated 1.2-5.5 million people are envenomed by snakebites annually. More than 125,000 of these bites are fatal, and 3-4 times as many results in disability/disfigurement. Despite its prevalence, collecting accurate epidemiological data on snakebite is challenging. This systematic review and meta-analysis collates global epidemiology data on snakebite morbidity and mortality. METHODS: Medline, Embase, Cochrane and CINAHL Plus databases were searched for articles published between 2001-2022. Pooled incidence and mortality were obtained using random effects modelling, heterogeneity (I2) was tested, and sensitivity analyses performed. Newcastle-Ottawa Scale assessed study quality. RESULTS: Out of the four databases, 5,312 articles were found. After removing duplicates, 3,953 articles were screened by title and abstract and 65 articles containing information on snakebite epidemiology, encompassing 663,460 snakebites, were selected for analysis. The people most at risk for snakebite were men (59%), engaged in agricultural labour (27.5%), and residing in rural areas (66.7%). More than half (57%) of the reported bites resulted in envenoming. Incidents occurred frequently in the summer season (38.5%), during daytime (56.7%), and bites were most often to the lower limb (56.4%). Envenoming severity was frequently mild (46.7%), treated in hospital (68.3%), and was treated with anti-venom (64.7%). The pooled global incidence and mortality was 69.4 /100,000 population (95%CI: 36.8 to 101.9) and 0.33/100,000 population (95%CI, 0.14 to 0.52) per year, respectively. Stratified by continents, Asia had the highest incidence of 130.7/100,000 population (95%CI: 48.3 to 213.1) while Europe has the lowest with 0.7/100,000 population (95%CI: -0.2 to 1.5). The highest mortality was reported in Asia at 0.96/100,000 population (95% CI: 0.22 to 1.70), and Africa 0.44/100,000 population (95%CI: -0.03 to 0.84). Incidence was highest among inhabitants of lower-middle-income countries 132.7/100,000 population (95%CI: 55.4 to 209.9) while mortality was highest in low-income countries at 0.85/100,000 population (95% CI: -0.06 to 2.31). CONCLUSION: Incidence and mortality rates noted here highlight the global impact of snakebite and underscore the critical need to address the burden of snakebite envenoming. It also reveals that while reported snakebite incidence was higher in lower-middle-income countries, the burden of mortality was greatest among inhabitants of low-income countries, again emphasising the need for greater efforts to tackle this neglected tropical disease.

The use of rotational thromboelastometry to guide management following Bitis nasicornis envenoming.

A man in his thirties presented following Bitis nasicornis envenoming. His coagulation was assessed using rotational thromboelastometry (ROTEM). It identified a subtle abnormality, not detected using standard laboratory assessments of coagulation, and influenced ongoing management. The abnormality resolved following treatment with antivenom. There are few documented cases of using ROTEM to assess patients following haemotoxic envenoming. This case highlights some of the potential benefits and limitations of doing so.

Protobothrops jerdonii (Jerdon's pit viper) and Protobothrops himalayanus (Himalayan lance-headed pit viper) bites: Clinical report on envenomings from North-East India, managed through remote consultation by a national-level Poison control center.

Members of the genus Protobothrops are amongst the more than twenty-eight range-restricted Indian pit viper species. Their bites and envenomings are rarely documented from India. Pit viper envenomings can be challenging to treat in the Indian setting, since available antivenoms do not satisfactorily neutralize their venoms. Herein, we present the first Indian reports on bites and envenoming by Protobothrops jerdonii and Protobothrops himalayanus resulting in local effects, coagulopathy and acute kidney injury in the case of the former and possible mild, isolated coagulopathy in the case of the latter; and discuss management-related challenges in the context of absent specific antivenoms.

First case of envenomation in humans caused by the banded cat-eyed snake Leptodeira annulata (Linnaeus, 1758) (Squamata: Dipsadidae) in Brazil.

A 22-year-old female researcher was bitten by a Leptodeira annulata on the index finger of the left hand during a contention activity. After removing the snake, a little bleeding and redness was observed in the bite region, accompanied by fang marks. Thirty minutes later, edema had progressed to the dorsum of the hand. After four hours, edema persisted, but the bitten area was slightly whitened. Treatment consisted of antibiotics and anti-inflammatory drugs. The edema resolved completely and disappeared after 48 hours. Overall, this report presents the first case of envenomation in humans caused by Leptodeira annulata in Brazil.

Biochemical and toxicological profiles of venoms from an adult female South American bushmaster (Lachesis muta rhombeata) and her offspring.

In this work, we compared the biochemical and toxicological profiles of venoms from an adult female specimen of Lachesis muta rhombeata (South American bushmaster) and her seven offspring born in captivity, based on SDS-PAGE, RP-HPLC, enzymatic, coagulant, and hemorrhagic assays. Although adult and juvenile venoms showed comparable SDS-PAGE profiles, juveniles lacked some chromatographic peaks compared with adult venom. Adult venom had higher proteolytic (caseinolytic) activity than juvenile venoms (p < 0.05), but there were no significant inter-venom variations in the esterase, PLA2, phosphodiesterase and L-amino acid oxidase (LAAO) activities, although the latter activity was highly variable among the venoms. Juveniles displayed higher coagulant activity on human plasma, with a minimum coagulant dose ∼42% lower than the adult venom (p < 0.05), but there were no age-related differences in thrombin-like activity. Adult venom was more fibrinogenolytic (based on the rate of fibrinogen chain degradation) and hemorrhagic than juvenile venoms (p < 0.05). The effective dose of Bothrops/Lachesis antivenom (produced by the Instituto Butantan) needed to neutralize the coagulant activity was ∼57% greater for juvenile venoms (p < 0.05), whereas antivenom did not attenuate the thrombin-like activity of juvenile and adult venoms. Antivenom significantly reduced the hemorrhagic activity of adult venom (400 µg/kg, i. d.), but not that of juvenile venoms. Overall, these data indicate a compositional and functional ontogenetic shift in L. m. rhombeata venom.

Long-term hospital care needs after Bothrops atrox envenomation with hemorrhagic stroke in the Brazilian Amazon: 'From social to physical death' - A case report.

Hemorrhagic stroke is a severe complication reported in cases of Bothrops atrox snakebite envenomation. We report an unusual case of a patient who evolved with an intracranial hemorrhagic stroke and was in a coma for more than five years in a tertiary hospital located in Manaus, Amazonas. 52-year-old man, carpenter, resident in the rural area of the municipality of Tabatinga, located 1106 km from Manaus, capital of Amazonas, Brazil, victim of an accident involving Bothrops atrox evolution with cardiorespiratory arrest, acute kidney injury and hemorrhagic stroke. After 43 days of hospitalization in the ICU, he was transferred to the ward, without contact with the environment and family, sent for home treatment, however, without acceptance by family members. During a long hospital stay for a period of 6 years, totally dependent on special care, in a flexed position, using a tracheostomy and mechanical ventilation, diagnosed and treated for hospital infections throughout his hospitalization, he died due to bacterial pneumonia. Losses of autonomy can result in an individual being completely disconnected from social life - a "social death before physical death".

Capacity of community health centers to treat snakebite envenoming in indigenous territories of the Brazilian Amazon.

INTRODUCTION: The deaths from and morbidities associated with snakebites - amputations, loss of function in the limb, visible scarring or tissue damage - have a vast economic, social, and psychological impact on indigenous communities in the Brazilian Amazon, especially children, and represent a real and pressing health crisis in this population. Snakebite clinical and research experts have therefore proposed expanding antivenom access from only hospitals to include the community health centers (CHC) located near and within indigenous communities. However, there are no studies examining the capacity of CHCs to store, administer, and manage antivenom treatment. In response to this gap, the research team calling for antivenom decentralization developed and validated an expert-based checklist outlining the minimum requirements for a CHC to provide antivenom. METHODS: The objective of this study was thus to survey a sample of CHCs in indigenous territories and evaluate their capacity to provide antivenom treatment according to this accredited checklist. The checklist was administered to nurses and doctors from 16 CHCs, two per indigenous district in Amazonas/Roraima states. RESULTS: Our results can be conceptualized into three central findings: 1) most CHCs have the capacity to provide antivenom treatment, 2) challenges to capacity are human resources and specialized items, and 3) antivenom decentralization is feasible and appropriate in indigenous communities. CONCLUSION: Decentralization would provide culturally and contextually appropriate care accessibility to a historically marginalized and underserved population of the Brazilian Amazon. Future studies should examine optimal resource allocation in indigenous territories and develop an implementation strategy in partnership with indigenous leaders. Beyond the indigenous population, the checklist utilized could be applied to community health centers treating the general population and/or adapted to other low-resource settings.

A Comparison of the Efficacy of Antivenoms and Varespladib against the In Vitro Pre-Synaptic Neurotoxicity of Thai and Javanese Russell's Viper (Daboia spp.) Venoms.

The heterogeneity in venom composition and potency in disparate Eastern Russell's viper (Daboia siamensis) populations has repercussions for the efficacy of antivenoms. This is particularly pronounced in geographical areas in which the venom of the local species has not been well studied and locally produced antivenoms are unavailable. In such cases, alternative therapies following envenoming, which are not limited by species specificity, may be employed to complement antivenoms. We studied the neuromuscular activity of D. siamensis venom from Thailand and Java (Indonesia) and the ability of Thai antivenoms and/or Varespladib to prevent or reverse these effects. Both Thai and Javanese D. siamensis venoms displayed potent pre-synaptic neurotoxicity but weak myotoxicity in the chick biventer cervicis nerve-muscle preparation. Whilst the neurotoxicity induced by both venoms was abolished by the prior administration of Thai D. siamensis monovalent antivenom or pre-incubation with Varespladib, Thai neuro-polyvalent antivenom only produced partial protection when added prior to venom. Pre-synaptic neurotoxicity was not reversed by the post-venom addition of either antivenom 30 or 60 min after either venom. Varespladib, when added 60 min after venom, prevented further inhibition of indirect twitches. However, the subsequent addition of additional concentrations of Varespladib did not result in further recovery from neurotoxicity. The combination of Thai monovalent antivenom and Varespladib, added 60 min after venom, resulted in additional recovery of twitches caused by either Thai or Javanese venoms compared with antivenom alone. In conclusion, we have shown that Varespladib can prevent and partially reverse the pre-synaptic neurotoxicity induced by either Thai or Javanese D. siamensis venoms. The efficacy of Thai D. siamensis monovalent antivenom in reversing pre-synaptic neurotoxicity was significantly enhanced by its co-administration with Varespladib. Further work is required to establish the efficacy of Varespladib as a primary or adjunct therapy in human envenoming.

Characterization of Sodium Channel Peptides Obtained from the Venom of the Scorpion Centruroides bonito.

Five peptides were isolated from the venom of the Mexican scorpion Centruroides bonito by chromatographic procedures (molecular weight sieving, ion exchange columns, and HPLC) and were denoted Cbo1 to Cbo5. The first four peptides contain 66 amino acid residues and the last one contains 65 amino acids, stabilized by four disulfide bonds, with a molecular weight spanning from about 7.5 to 7.8 kDa. Four of them are toxic to mice, and their function on human Na+ channels expressed in HEK and CHO cells was verified. One of them (Cbo5) did not show any physiological effects. The ones toxic to mice showed that they are modifiers of the gating mechanism of the channels and belong to the beta type scorpion toxin (ß-ScTx), affecting mainly the Nav1.6 channels. A phylogenetic tree analysis of their sequences confirmed the high degree of amino acid similarities with other known bona fide ß-ScTx. The envenomation caused by this venom in mice is treated by using commercially horse antivenom available in Mexico. The potential neutralization of the toxic components was evaluated by means of surface plasmon resonance using four antibody fragments (10FG2, HV, LR, and 11F) which have been developed by our group. These antitoxins are antibody fragments of single-chain antibody type, expressed in E. coli and capable of recognizing Cbo1 to Cbo4 toxins to various degrees.

Bothrops lanceolatus Envenoming in Martinique: A Historical Perspective of the Clinical Effectiveness of Bothrofav Antivenom Treatment.

Bothrofav, a monospecific antivenom, was introduced in June 1991 and has shown excellent effectiveness against life-threatening and thrombotic complications of Bothrops lanceolatus envenoming. Because of the reoccurrence of cerebral stroke events despite the timely administration of antivenom, new batches of Bothrofav were produced and introduced into clinical use in January 2011. This study's aim was to evaluate the effectiveness of Bothrofav generations at treating B. lanceolatus envenoming. During the first period of the study (2000-2010), 107 patients were treated with vials of antivenom produced in June 1991, while 282 envenomed patients were treated with vials of antivenom produced in January 2011 in the second study period (2011-2023). Despite timely antivenom administration, thrombotic complications reoccurred after an interval free of thrombotic events, and a timeframe analysis suggested that the clinical efficacy of Bothrofav declined after it reached its 10-year shelf-life. In of the case of an antivenom shortage due to the absence of regular batch production, no adverse effects were identified before the antivenom reached its 10-year shelf-life, which is beyond the accepted shelf-life for a liquid-formulation antivenom. While our study does not support the use of expired antivenom for potent, life-threatening B. lanceolatus envenoming, it can be a scientific message to public entities proving the necessity of new antivenom production for B. lanceolatus envenoming.

Immunochemical Recognition of Bothrops rhombeatus Venom by Two Polyvalent Antivenoms.

The protein profile of Bothrops rhombeatus venom was compared to Bothrops asper and Bothrops atrox, and the effectiveness of antivenoms from the National Institute of Health of Colombia (INS) and Antivipmyn-Tri (AVP-T) of Mexico were analyzed. Protein profiles were studied with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and reverse-phase high-performance liquid chromatography (RP-HPLC). The neutralizing potency and the level of immunochemical recognition of the antivenoms to the venoms were determined using Western blot, affinity chromatography, and enzyme-linked immunosorbent assay (ELISA). Bands of phospholipase A2 (PLA2), metalloproteinases (svMPs) I, II, and III as well as serine proteinases (SPs) in the venom of B. rhombeatus were recognized by SDS-PAGE. With Western blot, both antivenoms showed immunochemical recognition towards PLA2 and svMP. INS showed 94% binding to B. rhombeatus venom and 92% to B. asper while AVP-T showed 90.4% binding to B. rhombeatus venom and 96.6% to B. asper. Both antivenoms showed binding to PLA2 and svMP, with greater specificity of AVP-T towards B. rhombeatus. Antivenom neutralizing capacity was calculated by species and mL of antivenom, finding the following for INS: B. asper 6.6 mgV/mL, B. atrox 5.5 mgV/mL, and B. rhombeatus 1.3 mgV/mL. Meanwhile, for AVP-T, the following neutralizing capacities were found: B. asper 2.7 mgV/mL, B. atrox 2.1 mgV/mL, and B. rhombeatus 1.4 mgV/mL. These results show that both antivenoms presented similarity between calculated neutralizing capacities in our trial, reported in a product summary for the public for the B. asper species; however, this does not apply to the other species tested in this trial.

A Complex Pattern of Gene Expression in Tissue Affected by Viperid Snake Envenoming: The Emerging Role of Autophagy-Related Genes.

Viperid snake venoms induce severe tissue damage, characterized by the direct toxic action of venom components, i.e., phospholipases A2 (PLA2s) and metalloproteinases (SVMPs), concomitantly with the onset of endogenous inflammatory processes, in an intricate scenario of tissue alterations. Understanding the expression of relevant genes in muscle tissue will provide valuable insights into the undergoing pathological and inflammatory processes. In this study, we have used the Nanostring technology to evaluate the patterns of gene expression in mouse skeletal muscle 1 h, 6 h, and 24 h after injection of the venoms of Bothrops asper and Daboia russelii, two medically relevant species in Latin America and Asia, respectively, with somewhat different clinical manifestations. The dose of venoms injected (30 µg) induced local pathological effects and inflammation in muscle tissue. We focused our analysis on genes related to extracellular matrix (ECM) metabolism, immune system, programmed cell death, and autophagy. The results revealed a complex pattern of expression of genes. Regarding ECM metabolism and regulation, up-regulated genes included proteinase inhibitor Serpine 1, thrombospondin 1, collagens 1A1 and 4A1 (at 1 h in the case of B. asper), TIMP1, MMP-3 (at 24 h), and lysil oxidase (LOX). In contrast, collagen chains 5A3 and 5A1 were down-regulated, especially at 6 h. Transforming growth factor ß (TGF-ß) and several genes related to myofibroblast regulation were also up-regulated, which might be related to the development of fibrosis. Several genes related to cytokine and chemokine synthesis and regulation and NFκB signaling were also up-regulated. Our observations show a variable expression of genes associated with programmed cell death and autophagy, thus revealing a hitherto unknown role of autophagy in tissue affected by snake venoms. These results provide clues to understanding the complex pattern of gene expression in tissue affected by viperid snake venoms, which likely impacts the final pathophysiology of damaged tissue in envenomings.

Landscape of toxin-neutralizing therapeutics for snakebite envenoming (2015-2022): Setting the stage for an R&D agenda.

BACKGROUND: Progress in snakebite envenoming (SBE) therapeutics has suffered from a critical lack of data on the research and development (R&D) landscape. A database characterising this information would be a powerful tool for coordinating and accelerating SBE R&D. To address this need, we aimed to identify and categorise all active investigational candidates in development for SBE and all available or marketed products. METHODOLOGY/PRINCIPAL FINDINGS: In this landscape study, publicly available data and literature were reviewed to canvas the state of the SBE therapeutics market and research pipeline by identifying, characterising, and validating all investigational drug and biologic candidates with direct action on snake venom toxins, and all products available or marketed from 2015 to 2022. We identified 127 marketed products and 196 candidates in the pipeline, describing a very homogenous market of similar but geographically bespoke products and a diverse but immature pipeline, as most investigational candidates are at an early stage of development, with only eight candidates in clinical development. CONCLUSIONS/SIGNIFICANCE: Further investment and research is needed to address the shortfalls in products already on the market and to accelerate R&D for new therapeutics. This should be accompanied by efforts to converge on shared priorities and reshape the current SBE R&D ecosystem to ensure translation of innovation and access.

In vitro immunoreactivity and in vivo neutralization of Trimeresurus gracilis venom with antivenoms targeting four pit viper species.

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.

Anti-inflammatory, healing and antiophidic potential of Jatropha mollissima (Pohl) Baill. (Euphorbiaceae): From popular use to pharmaceutical formulation in gel.

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.