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Challenging paradigms is risky business: reflections on C. C. Snyder's "A definitive study of snakebite" --a commentary.

Recent improvements in research technologies for protein purification have expanded our understanding of the molecular and cellular toxins that comprise snake venoms. Many findings have suggested novel strategies for drug development and inspired renewed respect for the finesse with which snakes—and snake venoms—have evolved. Despite advances in basic science venom research, a universally accepted animal model for comparing different therapies for treating snake venom poisoning has not been established. Many animal models remain problematic in both design and execution. Results from experiments using mammalian surrogates pose challenges for the clinician interested in extrapolating results from the animal laboratory to the emergency department. For example, many studies performed between the 1950s and the late 1970s made use of age-, sex-, and mass-matched canines, an in vivo model that often requires a large sample size due to heterogeneity between animals. In contrast, experiments using pigs benefit from mass and physiologic responses that are comparable to those of humans. Unfortunately, the high costs of husbandry and test animals force many studies to operate with marginal sample sizes and an abbreviated period of experimental monitoring. Rabbit studies offer the advantage of lower cost, while serving as an established model for studies on complement and TH1 cytokine derangement, 2 intriguing methods with which snake venom appears to induce hemodynamic instability in the envenomated animal. Unfortunately, rabbits possess unacceptable intrinsic resistance to the venoms of many New World pit vipers, making comparisons with human patients difficult. The controversy surrounding the accuracy of envenomation research is not limited to animal experimentation. For example, many bench-top studies make use of lyophilized venom obtained from large wholesalers, who in turn obtain venom from a wide range of sources. Despite assurances from suppliers of freeze-dried venoms, such preparations are often contaminated with foreign proteases, venom degradation products, snake gland epithelial cells, and cytokine-inducing lipopolysaccharide. Indeed, our in vivo studies have provided growing evidence that natural venoms, obtained directly from captive-bred Southeast Asian elapids, are more potent and produce more complex chromatography profiles than lyophilized preparations obtained from the same colony animals. The point is important in that many animal studies performed