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Thai Russell's viper monospecific antivenom is immunoreactive and effective in neutralizing the venom of Daboia siamensis from Java, Indonesia

Lingam TMC, Tan KY, Tan CH

Toxicon, 2019 Oct;168:95-97.
PMID: 31254600 DOI: 10.1016/j.toxicon.2019.06.227

Daboia siamensis monovalent antivenom (DSMAV, Thailand) exhibited comparable immunoreactivity toward the venoms of eastern Russell's vipers from Thailand and Indonesia. It also effectively neutralized the procoagulant and lethal effects of both venoms, showing high potency. The Indonesian heterologous trivalent antivenom SABU (Serum Anti Bisa Ular), however, has very weak immunoreactivity and it failed to neutralize the Russell's viper venoms. DSMAV appears to be the appropriate choice of antivenom to treat Russell's viper envenoming.
Fulltext Proteomics and antivenom immunoprofiling of Russell's viper (Daboia siamensis) venoms from Thailand and Indonesia

Lingam TMC, Tan KY, Tan CH

J Venom Anim Toxins Incl Trop Dis, 2020;26:e20190048.
PMID: 32082369 DOI: 10.1590/1678-9199-JVATITD-2019-0048

The Eastern Russell's viper, Daboia siamensis, is a WHO Category 1 medically important venomous snake. It has a wide but disjunct distribution in Southeast Asia. The specific antivenom, D. siamensis Monovalent Antivenom (DsMAV-Thailand) is produced in Thailand but not available in Indonesia, where a heterologous trivalent antivenom, Serum Anti Bisa Ular (SABU), is used instead. This study aimed to investigate the geographical venom variation of D. siamensis from Thailand (Ds-Thailand) and Indonesia (Ds-Indonesia), and the immunorecognition of the venom proteins by antivenoms.
Methods: The venom proteins were decomplexed with reverse-phase high-performance liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, followed by in-solution tryptic digestion, nano-liquid chromatography-tandem mass spectrometry and protein identification. The efficacies of DsMAV-Thailand and SABU in binding the various venom fractions were assessed using an enzyme-linked immunosorbent assay optimized for immunorecognition profiling.
Results: The two most abundant protein families in Ds-Thailand venom are phospholipase A2 (PLA2) and Kunitz-type serine protease inhibitor (KSPI). Those abundant in Ds-Indonesia venom are PLA2 and serine protease. KSPI and vascular endothelial growth factor were detected in Ds-Thailand venom, whereas L-amino acid oxidase and disintegrin were present in Ds-Indonesia venom. Common proteins shared between the two included snaclecs, serine proteases, metalloproteinases, phosphodiesterases, 5'nucleotidases and nerve growth factors at varying abundances. DsMAV-Thailand exhibited strong immunorecognition of the major protein fractions in both venoms, but low immunoreactivity toward the low molecular weight proteins e.g. KSPI and disintegrins. On the other hand, SABU was virtually ineffective in binding all fractionated venom proteins.
Conclusion: D. siamensis venoms from Thailand and Indonesia varied geographically in the protein subtypes and abundances. The venoms, nevertheless, shared conserved antigenicity that allowed effective immunorecognition by DsMAV-Thailand but not by SABU, consistent with the neutralization efficacy of the antivenoms. A specific, appropriate antivenom is needed in Indonesia to treat Russell's viper envenomation.
Capillary leak syndrome induced by the venoms of Russell's Vipers (Daboia russelii and Daboia siamensis) from eight locales and neutralization of the differential toxicity by three snake antivenoms

Lingam TMC, Tan KY, Tan CH

Comp Biochem Physiol C Toxicol Pharmacol, 2021 Dec;250:109186.
PMID: 34508870 DOI: 10.1016/j.cbpc.2021.109186

Snakebite envenomation caused by the Western and Eastern Russell's Vipers (Daboia russelii and Daboia siamensis) may potentially induce capillary leak syndrome (CLS), while the use of antivenom in treating this has not been well examined. This study investigated the CLS-inducing toxicity of Russell's Viper venoms from various sources and examined the neutralization activity of regionally available antivenoms, using a newly devised mouse model. D. russelii venoms demonstrated a more consistent vascular leakage activity (76,000-86,000 CLS unit of vascular leak index, a function of the diameter and intensity of Evans Blue dye extravasation into dermis) than D. siamensis venoms (33,000-88,000 CLS unit). Both species venoms increased hematocrits markedly (53-67%), indicating hemoconcentration. Regional antivenoms (DsMAV-Thailand, DsMAV-Taiwan, VPAV-India) preincubated with the venoms effectively neutralized the CLS effect to different extents. When the antivenoms were administered intravenously post-envenomation (challenge-rescue model), the neutralization was less effective, implying that CLS has a rapid onset that preceded the neutralizing activity of antivenom, and/or the antivenom has limited biodistribution to the venom's inoculation site. In conclusion, Russell's Viper venoms of both species from various locales induced CLS in mice. Antivenoms generally had limited efficacy in neutralizing the CLS effect. Innovative treatment for venom-induced CLS is needed.
Varespladib (LY315920) rescued mice from fatal neurotoxicity caused by venoms of five major Asiatic kraits (Bungarus spp.) in an experimental envenoming and rescue model

Tan CH, Lingam TMC, Tan KY

Acta Trop, 2021 Dec 18;227:106289.
PMID: 34929179 DOI: 10.1016/j.actatropica.2021.106289

The venoms of Asiatic kraits (Bungarus spp.) contain various neurotoxic phospholipases A2 (beta-bungarotoxins) which can irreversibly damage motor nerve terminals, resulting in rapidly fatal suffocation by respiratory muscle paralysis or oral airway obstruction. Hence, there is a need of adjunct therapy at the pre-hospital stage to prevent or delay the onset of neurotoxicity, so that antivenom can be given within golden hour before the envenoming becomes antivenom-resistant. This study investigated the efficacy of varespladib, a small molecule PLA2 (phospholipase A2) inhibitor, given as a bolus subcutaneously upon the onset of krait venom-induced paralysis in a mouse experimental envenoming and rescue model, where the severity of neurotoxicity was scored and the survival rate was monitored over 24 h. Varespladib at 10 mg/kg effectively alleviated the neurotoxicity of Bungarus sindanus, Bungarus multicinctus and Bungarus fasciatus venoms, and rescued all mice from venom-induced lethality (100% survival). Varespladib at this dose, however, only partially reduced the neurotoxicity of Bungarus caeruleus and Bungarus candidus venoms, while all challenged mice were dead by 23 h (B. caeruleus) and 12 h (B. candidus). An increased dose of varespladib at 20 mg/kg markedly abated the venom neurotoxicity past 8 h of envenoming, and protected the mice from venom lethality (B. caeruleus: 75% survival; B. candidus: 100% survival). The finding is consistent with previous studies which demonstrated varespladib's inhibitory effect against some snake venoms. The findings suggest varespladib could be repurposed as an emergency drug for prevention or rescue (if given early enough) from the acute, neurotoxic envenoming syndromes caused by various major krait species in Asia.