Evaluation of the geographical utility of Eastern Russell’s viper (Daboia siamensis) antivenom from Thailand and an assessment of its protective effects against venom-induced nephrotoxicity

Abstract

BackgroundDaboia siamensis(Eastern Russell’s viper) is a medically important snake species found widely distributed across Southeast Asia. Envenomings by this species can result in systemic coagulopathy, local tissue injury and/or renal failure. While administration of specific antivenom is an effective treatment for Russell’s viper envenomings, the availability of, and access to, geographically-appropriate antivenom remains problematic in many rural areas. In this study, we determined the binding and neutralizing capability of antivenoms manufactured by the Thai Red Cross in Thailand againstD. siamensisvenoms from three geographical locales: Myanmar, Taiwan and Thailand.Methodology/ Principle findingsTheD. siamensismonovalent antivenom displayed extensive recognition and binding to proteins found inD. siamensisvenom, irrespective of the geographical origin of those venoms. Similar immunological characteristics were observed with the Hemato Polyvalent antivenom, which also usesD. siamensisvenom as an immunogen, but binding levels were dramatically reduced when using comparator monovalent antivenoms manufactured against different snake species. A similar pattern was observed when investigating neutralization of coagulopathy, with the procoagulant action of all three geographical venom variants neutralized by both theD. siamensismonovalent and the Hemato Polyvalent antivenoms, while the comparator monovalent antivenoms were ineffective. Assessments ofin vivonephrotoxicity revealed thatD. siamensisvenom (700 µg/kg) significantly increased plasma creatinine and blood urea nitrogen levels in anaesthetised rats. The intravenous administration ofD. siamensismonovalent antivenom at three times higher than the recommended scaled therapeutic dose, prior to and 1 h after the injection of venom, resulted in reduced levels of markers of nephrotoxicity, although lower doses had no therapeutic effect.Conclusions/SignificanceThis study highlights the potential broad geographical utility of the ThaiD. siamensismonovalent antivenom for treating envenomings by the Eastern Russell’s viper. However, only the early delivery of high antivenom doses appear capable of preventing venom-induced nephrotoxicity.Author summarySnakebite is a major public health concern in rural regions of the tropics. The Eastern Russell’s viper (Daboia siamensis) is a medically important venomous snake species that is widely distributed in Southeast Asia and Southern China, including Taiwan. Envenoming byD. siamensiscauses several systemic pathologies, most notably acute kidney failure and coagulopathy. The administration of antivenom is the mainstay therapeutic for treating snakebite, but in remote areas of Myanmar and Southern China access to antivenom is limited, and can result in the use of inappropriate, non-specific, antivenoms and treatment failure. Therefore, maximizing the utility of available efficacious antivenom is highly desirable. In this study, we investigated the utility of the widely available Thai Red Cross antivenoms for binding to and neutralizingD. siamensisvenoms sourced from three distinct locales in Asia. Since the effectiveness and antivenom dose required to preventD. siamensisvenom-induced nephrotoxicity has been controversial, we also examined the preclinical efficacy ofD. siamensisantivenom at preventing this pathology in experimentally envenomed anaesthetised animals. Our findings suggest that monovalent antivenom from Thailand, which is clinically effective in this country, has highly comparable levels of immunological binding andin vitroneutralization toD. siamensisvenoms from Taiwan and Myanmar. We also show that the early administration of high therapeutic doses of antivenom are likely required to neutralize nephrotoxins and thus prevent acute renal failure following envenoming. Our findings suggest that certain Thai Red Cross antivenoms likely have wide geographical utility againstD. siamensisvenom and therefore may be useful tools for managing snakebite envenomings by this species in the absence of available locally manufactured therapeutics.

A Biochemical and Pharmacological Characterization of Phospholipase A2 and Metalloproteinase Fractions from Eastern Russell’s Viper (Daboia siamensis) Venom: Two Major Components Associated with Acute Kidney Injury

“…In the current study, we determined histopathological changes of mouse kidneys following intraperitoneal administration of venom or fractions (300 µg/kg) for 24 h. A moderate degree of histopathological lesions was detected as diffuse and/or focal glomeruli, and congestion of interstitial vessels and tubular injury. These are almost the same characteristics of kidney lesion as identified in previous studies using perfused rabbit kidneys [ 21 ] and rat in vivo experiments [ 27 ]. However, the degree of morphological changes observed in our present work could not be compared with previous work performed by our group due to the differences in species of experimental animal used and time of contact with venom or toxins.…”

Causes and Consequences of Snake Venom Variation

“…In South Asia, antivenom manufactured using Indian Russell’s viper ( Daboia russelii ) venom exhibits low neutralizing potencies against venom from Bangladeshi populations of the same species, suggesting that perhaps five to ten times the normal treatment dose might be needed for effective treatment [ 15 ]. Contrastingly, antivenom made in Thailand against the congeneric species Daboia siamensis appears to exhibit considerable cross-recognition of venoms from the same species found in distinct geographical locales [ 63 ]. In combination, these observations suggest that venom variation makes predictions of antivenom efficacy extremely problematic, although the application of ‘antivenomic’ approaches that quantify the depletion of chromatographically separated and mass spectrometrically identified venom toxins by antivenoms are gaining traction as a predictive technology to help address these challenges [ 64 ].…”

Comparison of Methods for Measuring Protein Concentration in Venom Samples

“…However, in complex, unknown mixtures, it is hard to correctly estimate this parameter, and thus the calculated values can be very different from the true ones. Nevertheless, this method is commonly used in snake venom studies [46][47][48].…”