Venomic analysis of the venoms of Naja nigricollis, N. katiensis, N. nubiae, N. mossambica, and N. pallida revealed similar compositional trends. The high content of cytotoxins and PLA(2)s may account for the extensive tissue necrosis characteristic of the envenomings by these species. The high abundance of a type I α-neurotoxin in N. nubiae may be responsible for the high lethal toxicity of this venom (in rodents). The ability of EchiTAb-Plus-ICP antivenom to immunodeplete and neutralize the venoms of African spitting cobras was assessed by antivenomics and neutralization tests. It partially immunodepleted 3FTx and PLA(2)s and completely immunodepleted SVMPs and CRISPs in all venoms. The antivenom neutralized the dermonecrotic and PLA(2) activities of all African Naja venoms, whereas lethality was eliminated in the venoms of N. nigricollis, N. mossambica, and N. pallida but not in those of N. nubiae and N. katiensis. The lack of neutralization of lethality of N. nubiae venom may be of medical relevance only in relatively populous areas of the Saharan region. The impaired activity of EchiTAb-Plus-ICP against N. katiensis may not represent a major concern. This species is sympatric with N. nigricollis in many regions of Africa, although very few bites have been attributed to it.

Parenteral administration of horse- and sheep-derived antivenoms constitutes the cornerstone in the therapy of envenomations induced by animal bites and stings. Depending on the type of neutralising molecule, antivenoms are made of: (i) whole IgG molecules (150 kDa), (ii) F(ab')(2) immunoglobulin fragments (100 kDa) or (iii) Fab immunoglobulin fragments (50 kDa). Because of their variable molecular mass, these three types of antivenoms have different pharmacokinetic profiles. Fab fragments have the largest volume of distribution and readily reach extravascular compartments. They are catabolised mainly by the kidney, having a more rapid clearance than F(ab')(2) fragments and IgG. On the other hand, IgG molecules have a lower volume of distribution and a longer elimination half-life, showing the highest cycling through the interstitial spaces in the body. IgG elimination occurs mainly by extrarenal mechanisms. F(ab')(2) fragments display a pharmacokinetic profile intermediate between those of Fab fragments and IgG molecules. Such diverse pharmacokinetic properties have implications for the pharmacodynamics of these immunobiologicals, since a pronounced mismatch has been described between the pharmacokinetics of venoms and antivenoms. Some venoms, such as those of scorpions and elapid snakes, are rich in low-molecular-mass neurotoxins of high diffusibility and large volume of distribution that reach their tissue targets rapidly after injection. In contrast, venoms rich in high-molecular-mass toxins, such as those of viperid snakes, have a pharmacokinetic profile characterised by a rapid initial absorption followed by a slow absorption process from the site of venom injection. Such delayed absorption has been linked with recurrence of envenomation when antibody levels in blood decrease. This heterogeneity in pharmacokinetics and mechanism of action of venom components requires a detailed analysis of each venom-antivenom system in order to determine the most appropriate type of neutralising molecule for each particular venom. Besides having a high affinity for toxicologically relevant venom components, an ideal antivenom should possess a volume of distribution as similar as possible to that of the toxins being neutralised. Moreover, high levels of neutralising antibodies should remain in blood for a relatively prolonged time to assure neutralisation of toxins reaching the bloodstream later in the course of envenomation, and to promote redistribution of toxins from extravascular compartments to blood. Additional studies are required on different venoms and antivenoms in order to further understand the pharmacokinetic-pharmacodynamic relationships of antibodies and their fragments and to optimise the immunotherapy of envenomations.

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The therapy of snakebite envenomation has been based on the parenteral administration of animal-derived antivenoms. Despite the success of this treatment at reducing the impact of snakebite mortality and morbidity, mostly due to their capacity to neutralize systemically-acting toxins, antivenoms are of relatively low efficacy in the prevention of venom-induced local tissue damage, which often leads to permanent disability. The issue of safety also remains a concern, particularly for some antivenoms which induce a relatively high incidence of adverse reactions. Consequently, there is a need to improve the therapy of snakebite envenomations on the following lines: (a) the technologies to produce antivenoms require improvements aimed at obtaining more refined preparations of higher efficacy and safety, while being affordable for the public health systems of developing countries. (b) The growing knowledge on the biochemistry and toxicology of snake venoms should pave the way for the identification of natural and synthetic inhibitors of venom toxins, particularly of those involved in local tissue pathology. Such inhibitors might become a highly effective therapeutic tool for the abrogation of venom-induced local tissue damage. (c) A better knowledge of the inflammatory events secondary to venom actions may open the possibility of modulating such response, in order to prevent further tissue damage and to promote successful tissue repair and regeneration. A global partnership, involving many participants and combining scientific, technological and public health actions, is required to achieve a leap forward in the treatment of snakebite envenomations world-wide.

Animal-derived antivenoms constitute the mainstay in the therapy of snakebite envenoming. The efficacy of antivenoms to neutralize toxicity of medically-relevant snake venoms has to be demonstrated through meticulous preclinical testing before their introduction into the clinical setting. The gold standard in the preclinical assessment and quality control of antivenoms is the neutralization of venom-induced lethality. In addition, depending on the pathophysiological profile of snake venoms, the neutralization of other toxic activities has to be evaluated, such as hemorrhagic, myotoxic, edema-forming, dermonecrotic, in vitro coagulant, and defibrinogenating effects. There is a need to develop laboratory assays to evaluate neutralization of other relevant venom activities. The concept of the 3Rs (Replacement, Reduction, and Refinement) in Toxinology is of utmost importance, and some advances have been performed in their implementation. A significant leap forward in the study of the immunological reactivity of antivenoms against venoms has been the development of “antivenomics”, which brings the analytical power of mass spectrometry to the evaluation of antivenoms. International partnerships are required to assess the preclinical efficacy of antivenoms against snake venoms in different regions of the world in order to have a detailed knowledge on the neutralizing profile of these immunotherapeutics.