Effect of the phospholipase A2 inhibitor Varespladib, and its synergism with crotalic antivenom, on the neuromuscular blockade induced by Crotalus durissus terrificus venom (with and without crotamine) in mouse neuromuscular preparations

Souza, J. de; Oliveira, Isadora Caruso Fontana; Yoshida, Edson Hideaki; Cantuaria, Nathalia Margarida; Cogo, José Carlos; Torres-Bonilla, Kristian A.; Hyslop, Stephen; Silva, Nelson J.; Floriano, Rafael Stuani; Gutiérrez, José Marı́a; Oshima-Franco, Yoko

doi:10.1016/j.toxicon.2022.05.001

Cited by 8 publications

(12 citation statements)

References 36 publications

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“…In our study, we found that pre-incubation with Varespladib prevented both the neurotoxic and myotoxic effects of D. siamensis venom, indicating the key role PLA 2 toxins play in these effects. Our findings support previous reports showing that Varespladib prevents PLA 2 -mediated neurotoxicity and myotoxicity across a diverse range of snake venoms [ 23 , 24 , 25 , 45 , 47 , 48 , 57 , 58 , 59 , 60 ]. The important role of PLA 2 toxins in Daboia spp .…”

Section: Discussionsupporting

confidence: 92%

“…However, the administration of a combination of antivenom and Varespladib after venom addition did not result in an additive or synergistic inhibitory effect against the neurotoxic or myotoxic effects. A similar finding of greater efficacy of Varespladib over antivenom has also been reported against O. scutellatus venom, an elapid venom with PLA 2 -mediated neurotoxicity [ 23 ], and C. d. terrificus venom, from a viperid with PLA 2 -mediated neurotoxicity and myotoxicity [ 24 , 25 ]. These observations support in vivo experiments in mice, where Varespladib was able to inhibit the myotoxic effects of four Chinese snake venoms [ 44 ] as well as attenuate the myonecrotic and haemorrhagic activity induced by Deinagkistrodon acutus (sharp-nosed pit viper) venom [ 46 ].…”

Section: Discussionsupporting

confidence: 68%

“…In this regard, the higher efficacy of Varespladib over antivenoms to inhibit the activity of these toxins may be due to (1) higher potency of Varespladib to inhibit PLA 2 activity at low concentrations; (2) the ability of Varespladib to bind with high affinity to neurotoxins and myotoxins, possibly displacing even those already bound extracellularly to their target sites or reducing affinity between toxin and substrate; or (3) the ability of Varespladib to enter the nerve terminal or cells, perhaps inhibiting intracellular snake venom PLA 2 s [ 20 , 23 , 24 ]. It is worth noting that while the progression of direct twitch inhibition induced by venom was halted, but not reversed, by Varespladib, baseline tension was restored to pre-venom levels.…”

Section: Discussionmentioning

confidence: 99%

“…Those present in elapids are categorised within group I, whereas those found in Viperidae venoms are within group II [ 21 , 22 ]. Such toxins have been reported to be responsible for neurotoxicity (i.e., taipoxin from Oxyuranus scutellatus, Coastal taipan) [ 16 , 23 ], myotoxicity (i.e., crotoxin from Crotalus durissus terrificus, South American rattlesnake) [ 24 , 25 ], pain and oedema, cardiovascular disturbances, haemolysis and coagulation disorders, amongst other effects [ 18 , 26 , 27 , 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

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

Lay

Liang²,

Hodgson³

2023

Toxins

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

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Lay

Liang²,

Hodgson³

2023

Toxins

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“…While the antivenom displayed slight efficacy in isolation against P. volcanicum , its use in combination with small-molecule inhibitors may improve the therapeutic potential. Indeed, several recent studies have shown the therapeutic synergy between small-molecule inhibitors and antivenom for a range of snake venoms [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

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

Jones

Youngman

Neri-Castro

et al. 2022

Toxins

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

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

Werner,

Soffa

2023

Toxicon: X

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Effect of the phospholipase A2 inhibitor Varespladib, and its synergism with crotalic antivenom, on the neuromuscular blockade induced by Crotalus durissus terrificus venom (with and without crotamine) in mouse neuromuscular preparations

Cited by 8 publications

References 36 publications

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

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

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

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

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