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      A First Look at the Inhibitory Potential of Urospatha sagittifolia (Araceae) Ethanolic Extract for Bothrops atrox Snakebite Envenomation

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          Abstract

          Bothrops atrox snakebites are a relevant problem in the Amazon basin. In this biodiverse region, the ethnomedicinal approach plays an important role as an alternative to antivenom therapy. Urospatha sagittifolia (Araceae) is a plant used for this purpose; however, its neutralizing properties have not been scientifically accessed. To fill this gap, we investigated the ability of U. sagittifolia to modulate the catalytic activity of Bothrops atrox venom, and their toxic consequences, such as local damage and lethality. The venom profile of B. atrox was assessed by chromatography and electrophoresis. Inhibition of the three main enzymatic and medically important toxins from the venom was evaluated using synthetic substrates and quantified by chromogenic activity assays. Additionally, the neutralization of lethality, hemorrhage and edema were investigated by in vivo assays. The possible interactions between venom proteins and plant molecules were visualized by polyacrylamide gel electrophoresis. Finally, the phytochemical constituents present in the ethanolic extract were determined by qualitative and quantitative analyses. The ethanolic extract reduced the activity of the three main enzymes of venom target, achieving ranges from 19% to 81% of inhibition. Our in vivo venom neuralizations assays showed a significant inhibition of edema (38.72%) and hemorrhage (42.90%). Additionally, lethality was remarkably counteracted. The highest extract ratio evaluated had a 75% survival rate. Our data support the biomedical value of U. sagittifolia as a source of natural enzyme inhibitors able to neutralize catalytically active B. atrox venom toxins and their toxic effects.

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          Snakebite envenoming

          Snakebite envenoming is a neglected tropical disease that kills >100,000 people and maims >400,000 people every year. Impoverished populations living in the rural tropics are particularly vulnerable; snakebite envenoming perpetuates the cycle of poverty. Snake venoms are complex mixtures of proteins that exert a wide range of toxic actions. The high variability in snake venom composition is responsible for the various clinical manifestations in envenomings, ranging from local tissue damage to potentially life-threatening systemic effects. Intravenous administration of antivenom is the only specific treatment to counteract envenoming. Analgesics, ventilator support, fluid therapy, haemodialysis and antibiotic therapy are also used. Novel therapeutic alternatives based on recombinant antibody technologies and new toxin inhibitors are being explored. Confronting snakebite envenoming at a global level demands the implementation of an integrated intervention strategy involving the WHO, the research community, antivenom manufacturers, regulatory agencies, national and regional health authorities, professional health organizations, international funding agencies, advocacy groups and civil society institutions.
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            Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation

            Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.
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              Snakebite envenoming from a global perspective: Towards an integrated approach.

              Snakebite envenoming is a neglected public health challenge of compelling importance in many regions of the world, particularly sub-Saharan Africa, Asia, Latin America and Papua-New Guinea. Addressing the problem of snakebite effectively demands an integrated multifocal approach, targeting complex problems and involving many participants. It must comprise: (a) Acquisition of reliable information on the incidence and mortality attributable to snakebite envenoming, and the number of people left with permanent sequelae. (b) Improvements in production of effective and safe antivenoms, through strategies aimed at strengthening the technological capacity of antivenom manufacturing laboratories. (c) Increasing the capacity of low-income countries to produce specific immunogens(snake venoms) locally, and to perform their own quality control of antivenoms. (d) Commitments from regional producers to manufacture antivenoms for countries where antivenom production is not currently feasible. (e) Implementation of financial initiatives guaranteeing the acquisition of adequate volumes of antivenom at affordable prices in low-income countries. (f) Performance of collaborative studies on the safety and effectiveness of antivenoms assessed preclinically and by properly designed clinical trials. (g) Development of antivenom distribution programmes tailored to the real needs and epidemiological situations of rural areas in each country. (h) Permanent training programmes for health staff, particularly in rural areas where snakebites are frequent.(i) Implementation of programmes to support those people whose snakebites resulted in chronic disabilities. (j) Preventive and educational programmes at the community level, with the active involvement of local organizations and employing modern methods of health promotion. Such an integrated approach, currently being fostered by the Global Snake Bite Initiative of the International Society on Toxinology and by the World Health Organization, will help to alleviate the enormous burden of human suffering inflicted by snakebite envenoming. Copyright © 2009 Elsevier Ltd. All rights reserved.
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                Journal
                TOXIB7
                Toxins
                Toxins
                MDPI AG
                2072-6651
                July 2022
                July 17 2022
                : 14
                : 7
                : 496
                Article
                10.3390/toxins14070496
                35878234
                9b176899-8286-41af-b9a9-d1001bcce8b1
                © 2022

                https://creativecommons.org/licenses/by/4.0/

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