Varespladib in the Treatment of Snakebite Envenoming: Development History and Preclinical Evidence Supporting Advancement to Clinical Trials in Patients Bitten by Venomous Snakes

Toxins, Journal Year: 2022, Volume and Issue: 14(11), P. 783 - 783

Published: Nov. 11, 2022

The availability of effective, reliably accessible, and affordable treatments for snakebite envenoming is a critical long unmet medical need. Recently, small, synthetic toxin-specific inhibitors with oral bioavailability used in conjunction antivenom have been identified as having the potential to greatly improve outcomes after snakebite. Varespladib, molecule that broadly potently inhibits secreted phospholipase A2 (sPLA2s) venom toxins has renewed interest this class due its utility treatment envenoming. development varespladib dosage form, varespladib-methyl, accelerated by previous clinical campaigns treat non-envenoming conditions related ulcerative colitis, rheumatoid arthritis, asthma, sepsis, acute coronary syndrome. To date, twenty-nine studies evaluating safety, pharmacokinetics (PK), efficacy non-snakebite completed more than 4600 human subjects, drugs were generally well-tolerated considered safe use humans. Since 2016, 30 publications describing structure, function, directly addressed This review summarizes preclinical findings outlines scientific support, limitations, next steps varespladib's treatment, which now Phase 2 trials United States India.

Language: Английский

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In Vitro Efficacy of Antivenom and Varespladib in Neutralising Chinese Russell’s Viper (Daboia siamensis) Venom Toxicity

Toxins, Journal Year: 2023, Volume and Issue: 15(1), P. 62 - 62

Published: Jan. 11, 2023

The venom of the Russell's viper (Daboia siamensis) contains neurotoxic and myotoxic phospholipase A2 toxins which can cause irreversible damage to motor nerve terminals. Due time delay between envenoming antivenom administration, antivenoms may have limited efficacy against some these components. Hence, there is a need for adjunct treatments circumvent limitations. In this study, we examined Chinese D. siamensis alone, in combination with PLA2 inhibitor, Varespladib, reversing vitro neuromuscular blockade chick biventer cervicis nerve-muscle preparation. Pre-synaptic neurotoxicity myotoxicity were not reversed by addition 30 or 60 min after (10 µg/mL). prior Varespladib prevented activity µg/mL) was also able prevent further reductions block muscle twitches when added venom. failed produce improvements than alone. This demonstrates that window remains effective relatively short compared small-molecule inhibitors be abrogating activities

Language: Английский

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Differential Antivenom and Small-Molecule Inhibition of Novel Coagulotoxic Variations in Atropoides, Cerrophidion, Metlapilcoatlus, and Porthidium American Viperid Snake Venoms

Toxins, Journal Year: 2022, Volume and Issue: 14(8), P. 511 - 511

Published: July 26, 2022

Within Neotropical pit-vipers, the Mexican/Central-American clade consisting of Atropoides, Cerrophidion, Metlapilcoatlus, and Porthidium is a wide-ranging, morphologically ecologically diverse group snakes. Despite their prevalence, little known functional aspects venoms. This study aimed to fill knowledge gap regarding coagulotoxic effects examine potential different therapeutic approaches. As general trait, venoms were shown be anticoagulant but underpinned by biochemical actions. Pseudo-procoagulant activity (i.e., thrombin-like), characterized direct cleavage fibrinogen form weak fibrin clots, was evident for Atropoides picadoi, Cerrophidiontzotzilorum, Metlapilcoatlus mexicanus, M. nummifer, occiduus, olmec, porrasi. In contrast, other cleaved in destructive (non-clotting) manner, with C. godmani wilsoni being most potent. addition actions on fibrinogen, clotting enzymes also inhibited. FXa only weakly inhibited species, Cerrophidion extremely strong inhibitory action. Other more widely species spanning full taxonomical range, each case, there that had these traits notably amplified relatively others. potent amongst those formation prothrombinase complex inhibitors Factor XIa. While displayed low levels thrombin inhibition, dunni potently this factor. The regional polyvalent antivenom produced Instituto Picado Clodomiro tested effective against pathophysiological effects. contrast activities volcanicum uniquely procoagulant through activation VII XII. viperid first snake outside Oxyuranus/Pseudonaja elapid activate FVII venom any kind FXII. Interestingly, while small-molecule metalloprotease prinomastat marimastat demonstrated ability prevent toxicity P. volcanicum, neither ICP nor inhibitor DMPS showed effect. extreme variation among snakes here studied underscores how dynamic trait can shape clinical outcomes influence evolving treatment strategies.

Language: Английский

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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

Toxins, Journal Year: 2024, Volume and Issue: 16(3), P. 124 - 124

Published: March 1, 2024

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

Language: Английский

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Considerations for the development of a field-based medical device for the administration of adjunctive therapies for snakebite envenoming

Toxicon X, Journal Year: 2023, Volume and Issue: 20, P. 100169 - 100169

Published: Aug. 19, 2023

The timely administration of antivenom is the most effective method currently available to reduce burden snakebite envenoming (SBE), a neglected tropical disease that often affects rural agricultural global populations. There increasing interest in development adjunctive small molecule and biologic therapeutics target problematic venom components bridge time-gap between initial SBE antivenom. Unique combinations these could provide relief from toxic effects regional groupings medically relevant snake species. application PRISMA/PICO literature search methodology demonstrated an rapid therapies improve patient symptoms outcomes after SBE. Advice expert interviews considerations regarding potential routes therapy administration, anatomical bite location, species-specific delivery have provided framework identify ideal metrics hurdles for field-based medical device be used immediately deliver therapies. use subcutaneous (SC) or intramuscular (IM) injection were identified as both

Language: Английский

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Biological and Medical Aspects Related to South American Rattlesnake Crotalus durissus (Linnaeus, 1758): A View from Colombia

Toxins, Journal Year: 2022, Volume and Issue: 14(12), P. 875 - 875

Published: Dec. 15, 2022

In Colombia, South America, there is a subspecies of the American rattlesnake Crotalus durissus, C. d. cumanensis, snake Viperidae family, whose presence has been reduced due to destruction its habitat. It an enigmatic from group pit vipers, venomous, with large articulated front fangs, special designs on body, and characteristic rattle tail. Unlike in Brazil, occurrence human envenomation by durisus Colombia very rare contributes less than 1% caused snakes. Its venom complex cocktail proteins different biological effects, which evolved purpose paralyzing prey, killing it, starting digestive process, as well having defense functions. When injected into humans result bite, victim presents both local tissue damage systemic involvement, including diverse degree neurotoxic, myotoxic, nephrotoxic, coagulopathic among others. effects are being studied for use health, possible development analgesic, muscle relaxant, anti-inflammatory, immunosuppressive, anti-infection, antineoplastic drugs. Several groups researchers Brazil active their contributions this regard. work, review made most relevant medical aspects related what may be importance better understanding present Venezuela.

Language: Английский

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In Silico Evaluation of Quercetin Methylated Derivatives on the Interaction with Secretory Phospholipases A2 from Crotalus durissus terrificus and Bothrops jararacussu

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(4), P. 597 - 597

Published: April 15, 2023

Quercetin derivatives have already shown their anti-inflammatory potential, inhibiting essential enzymes involved in this process. Among diverse pro-inflammatory toxins from snake venoms, phospholipase A2 is one of the most abundant some species, such as Crotalus durissus terrificus and Bothrops jararacussu Viperidae family. These can induce inflammatory process through hydrolysis at sn-2 position glycerophospholipids. Hence, elucidating main residues biological effects these macromolecules help to identify potential compounds with inhibitory activity. In silico tools were used study evaluate quercetin methylated inhibition bothropstoxin I (BthTX-I) II (BthTX-II) terrificus. The use a transitional analogous two classical inhibitors guided work find role phospholipid anchoring subsequent development First, cavities studied, revealing best regions be inhibited by compound. Focusing on regions, molecular docking assays made show interactions between each Results reveal that analogue inhibitors, Varespladib (Var) p-bromophenacyl bromide (BPB), quercetins analysis, Leu2, Phe5, Tyr28, glycine calcium-binding loop, His48, Asp49 BthTX-II Cdtspla2 inhibited. 3MQ exhibited great interaction active site, similar Var results, while Q anchored better site. However, strong C-terminal region, highlighting His120, seem crucial decreasing contacts BthTX-II. anchor differently toxin further vitro vivo studies are elucidate data.

Language: Английский

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Pathophysiological and Clinical Significance of Crotalus durissus cascavella Venom-Induced Pulmonary Impairment in a Murine Model

Toxins, Journal Year: 2023, Volume and Issue: 15(4), P. 282 - 282

Published: April 14, 2023

Crotalus venom has broad biological activity, including neurotoxic, myotoxic, hematologic, and cytotoxic compounds that induce severe systemic repercussions. We evaluated the pathophysiological clinical significance of durissus cascavella (Cdc) venom-induced pulmonary impairment in mice. conducted a randomized experimental study, involving 72 animals intraperitoneally inoculated with saline solution control group (CG), as well (EG). The were euthanized at predetermined intervals (1 h, 3 6 12 24 48 h), lung fragments collected for H&E Masson histological analysis. CG did not present inflammatory alterations parenchyma. In EG, interstitial alveolar swelling, necrosis, septal losses followed by distensions, areas atelectasis parenchyma observed after three hours. EG morphometric analysis presented infiltrates all time intervals, being more significant six (p = 0.035) h 0.006). necrosis zones one 0.001), 0.035). induces diffuse, heterogeneous, acute injury parenchyma, potential implications respiratory mechanics gas exchange. early recognition prompt treatment this condition are essential to prevent further improve outcomes.

Language: Английский

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