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Broadening the research landscape in the field of snakebite envenoming: towards a holistic perspective
(2023-09-01) Gutiérrez, José María; Bolon, Isabelle; Borri, Juliette Ildiko; Ruiz de Castañeda, Rafael Luis
Snakebite envenoming (SBE) is a neglected tropical disease that kills and maims hundreds of thousands of people yearly, particularly in impoverished rural settings of the Global South. Understanding the complexity of SBE and tackling this disease demands a transdisciplinary, One Health approach. There is a long-standing research tradition on SBE in toxinology and human medicine. In contrast, other disciplines, such as veterinary medicine or social sciences, still need to be better developed in this field, especially in countries with a high incidence of SBE. Broadening the disciplinary landscape, connecting various research approaches, methods, and data across disciplines and sectors, and engaging with communities affected by SBE in implementing evidence-based solutions are needed. This review summarizes areas that require strengthening to better understand the complexity of SBE and to generate a robust body of knowledge to be translated into effective public health interventions.
Neutralization, by a polyspecific antivenom, of the coagulopathy induced by the venom of Bothrops asper: assessment by standard coagulation tests and rotational thromboelastometry in a murine model
(2023-09-21) Camacho, Erika; Ramírez Vargas, Gabriel; Vargas, Karol; Rucavado Romero, Alexandra; Escalante Muñoz, Teresa; Vargas, Mariángela; Segura Ruiz, Álvaro; Argüello, Ivette; Campos, Marlen; Guerrero, German; Lamela Méndez, Marilla; Gutiérrez, José María
Venom-induced consumption coagulopathy and thrombocytopenia are common and potentially severe manifestations of viperid snakebite envenoming since they contribute to local and systemic hemorrhage. Therefore, the assessment of the efficacy of antivenoms to neutralize coagulopathic and thrombocytopenic toxins should be part of the preclinical evaluation of these drugs. To evaluate the efficacy of the polyvalent (Crotalinae) antivenom produced in Costa Rica, in this study we have used a mouse model of coagulopathy and thrombocytopenia induced by the venom of Bothrops asper, based on the bolus intravenous (i.v.) injection of venom. When venom and antivenom were incubated before injection, or when antivenom was administered i.v. immediately after venom injection, venom-induced hemostatic alterations were largely abrogated. We also studied the recovery rate of clotting parameters in conditions where antivenom was administered when mice were coagulopathic. Some parameters recovered more rapidly in antivenom-treated mice than in control envenomed animals, but others showed a spontaneous recovery without antivenom. This is due to a rapid clearance of plasma venom levels in these experimental conditions. This implies that models based on the bolus i.v. injection of venom have limitations for assessing the effect of antivenom in the recovery of clotting alterations once coagulopathy has developed. It is suggested that alternative models should be developed based on a slower systemic absorption of venom. Overall, our findings provide a protocol for the preclinical evaluation of antivenoms and demonstrate that the polyvalent antivenom is effective in neutralizing the toxins of B. asper venom responsible for coagulopathy and thrombocytopenia.
Systemic vascular leakage induced in mice by Russell’s viper venom from Pakistan
(2018-10-31) Rucavado Romero, Alexandra; Escalante Muñoz, Teresa; Camacho, Erika; Gutiérrez, José María; Fox, Jay W.
Envenomings by some populations of the Russell’s viper (Daboia russelii) are characterized by a systemic capillary leak syndrome (CLS) which causes hemoconcentration, and is associated with the severity of envenoming. We adapted a model of CLS in mice by assessing hemoconcentration. The venom of D. russelii from Pakistan, but not that of another viperid, Bothrops asper, induced hemoconcentration and an increment in vascular permeability, being devoid of hemorrhagic activity at the doses tested. These findings reveal a dichotomous pattern of vasculotoxicity in viperid snake venoms. This difference might depend on variations in venom composition, especially regarding metalloproteinases (SVMPs), which are low in Pakistani D. russelii and high in B. asper. Inhibition of SVMPs and phospholipases A2 in D. russelii venom did not abrogate hemoconcentration. An hemoconcentration-inducing fraction was obtained by chromatography, which contains vascular endothelial growth factor (VEGF), a known potent inducer of increment in vascular permeability. Exudates collected from tissue injected with venom also induced hemoconcentration, and the effect was inhibited by antivenom. However, the amount of venom in exudate required to induce the effect is low, as compared with venom dissolved in saline solution, hence suggesting that endogenous proteins present in the exudate, probably inflammatory mediators, potentiate the effect.
Assessment of the Artemia salina toxicity assay as a substitute of the mouse lethality assay in the determination of venom-induced toxicity and preclinical efficacy of antivenom
(2024-04-03) Araya Pizarro, Xavier Alberto; Okumu, Mitchel Otieno; Durán Blanco, Gina; Gómez Argüello, Aarón; Gutiérrez Gutiérrez, José María; León Montero, Guillermo
Mice are routinely used in snake venom research but are costly and subject to pain and suffering. The crustacean Artemia salina could be an alternative to mice, but data to support its adoption in snake venom research is limited. The aim of the present study was to evaluate the suitability of A. salina as a surrogate of mice in assessing the toxicity of venoms and the preclinical efficacy of antivenoms. The toxicity of venoms from 22 snakes of medical importance in sub–Saharan Africa was evaluated in mice (intraperitoneally; i.p. and intravenously; i.v.) and in A. salina. Subsequently, the capacity of a commercial antivenom to neutralize the toxicity of these venoms in mice and A. salina was investigated. There was a positive correlation between the i.v. median lethal doses (LD50s) and the i.p. LD50s in mice (r = 0.804; p < 0.0001), a moderate correlation between the i.v. LD50s in mice and the median lethal concentrations (LC50s) in A. salina (r = 0.606; p = 0.003), and a moderate correlation between the i.p. LD50s in mice and the LC50s in A. salina (r = 0.426; p = 0.048). Moreover, there was a strong correlation between the i.p. median effective doses (ED50s) and the i.v. ED50s in mice (r = 0.941, p < 0.0001), between the i.p. ED50s in mice and the ED50s in A. salina (r = 0.818, p < 0.0001), and between the i.v. ED50s in mice and the ED50s in A. salina (r = 0.972, p < 0.0001). These findings present A. salina as a promising candidate for reducing reliance on mice in snake venom research. Future investigations should build upon these findings, addressing potential limitations and expanding the scope of A. salina in venom research and antivenom development.
Surface complexation and reactivity of ferrihydrite in relation to its surface and mineral structure, with applications to natural systems
(2025-03-28) Hiemstra, Tjisse; Hofmann, Annette; Méndez Fernández, Juan Carlos; Bai, Yilina
Ferrihydrite (Fh) is the most important iron (hydr)oxide from the perspective of regulating the bioavailability and mobility of ions in the natural environment. Its existence was already known in the nineteenth century. Van Bemmelen and Klobbie (1892) studied the composition of what they called in French “Oxyde Ferrique Humide Amorphe” (Van Bemmelen and Klobbie 1896), being different from “Hydroxyde Ferrique Cristallin”. At about the same time (1895), X-rays were discovered by Wilhelm Conrad Röntgen, but their use for unraveling the structures of crystalline Fe (hydr)oxides and ferrihydrite was yet to come. In 1912, Max von Laue reported that...